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Introduction
Over decades, billions of dollars have been dedi-cated to the development of an AIDS vaccine, onlyto result in disappointment and failure (1, 2). Theexact number of vaccines tested pre-clinically andclinically is difficult to determine, but recentreviews have suggested over 30–40 vaccines in over85 clinical trials involving almost 20,000 volunteers(3–7). The US National Institute of Allergy andInfectious Diseases (NIAID) report over 50 preven-tive vaccines in over 100 clinical trials (8), and 30-plus therapeutic trials. This analysis indicates thatthe figures are even greater, with no vaccine affect-ing disease progression (9, 10) or approved for use.
Initial optimism, such as that shown in 1984when the US Health and Human Services secretarydeclared that a vaccine would be available withintwo years, has given way to a realisation that thevirus will not be beaten easily. In some quarters, itis acknowledged that animal models of questionablerelevance are culpable (for comprehensive citedexamples and examples of expert opinion, see [11]and other cited references throughout this review).These animal models include the use of macaquesinfected with Simian Immunodeficiency Virus (SIV)or hybrids of SIV and Human ImmunodeficiencyVirus (HIV). President Clinton’s 2007 goal for the
development of an AIDS vaccine has now passed,with notable high-profile failures such as VaxGen’sAIDSVAX and Merck’s V520 vaccines. In 2004, theAIDS Vaccine Advocacy Coalition (AVAC) acknowl-edged that there would be no vaccine available by2007, foreseeing a ‘long haul’ (12); and optimisticexperts predict that it will be over a decade beforethe first vaccine is available — while others predicthalf a century (13).
In the light of these statistics and recent high-profile failures, many scientists are advocatingchanges to AIDS vaccine development. A smallnumber involved in chimpanzee research believethat chimpanzees have been, and will remain,important, and thus advocate a return to their use(14).
This recommendation requires evidence thatchimpanzees played a crucial role when their use inthe late 1980s and early 1990s was common. This isthe scope of this study: to assess whether theirresponses to previous vaccines correlated withhuman responses and to compare the immunogenicand prophylactic natures of those vaccines in chim-panzees and humans. The a priori argument is thatif the vaccines behaved similarly, the resumed useof chimpanzees may be scientifically justifiable,independent of ethical considerations; but if thechimpanzee results proved erroneously predictive,there would be no scientific basis upon which to call
An Assessment of the Role of Chimpanzees in AIDSVaccine Research
Jarrod Bailey
New England Anti-Vivisection Society, Boston, MA, USA
Summary — Prior to Simian Immunodeficiency Virus (SIV)-infected macaques becoming the ‘model ofchoice’ in the 1990s, chimpanzees were widely used in AIDS vaccine research and testing. Faced with thecontinued failure to develop an effective human vaccine, some scientists are calling for a return to theirwidespread use. To assess the past and potential future contribution of chimpanzees to AIDS vaccine devel-opment, databases and published literature were systematically searched to compare the results of AIDSvaccine trials in chimpanzees with those of human clinical trials, and to determine whether the chimpanzeetrials were predictive of the human response. Protective and/or therapeutic responses have been elicited inchimpanzees, via: passive antibody transfer; CD4 analogues; attenuated virus; many types and combina-tions of recombinant HIV proteins; DNA vaccines; recombinant adenovirus and canarypox vaccines; andmany multi-component vaccines using more than one of these approaches. Immunogenicity has also beenshown in chimpanzees for vaccinia-based and peptide vaccines. Protection and/or significant therapeuticeffects have not been demonstrated by any vaccine to date in humans. Vaccine responses in chimpanzeesand humans are highly discordant. Claims of the importance of chimpanzees in AIDS vaccine developmentare without foundation, and a return to the use of chimpanzees in AIDS research/vaccine development isscientifically unjustifiable.
Key words: AIDS, chimpanzee, HIV, Pan troglodytes, vaccine.
Address for correspondence: J. Bailey, New England Anti-Vivisection Society, 333 Washington Street,Suite 850, Boston, MA 02108-5100, USA.E-mail: [email protected]
ATLA 36, 381–428, 2008 381
for the reinstatement of chimpanzees in AIDSresearch.
Summary of Vaccines and ClinicalTrials
A prerequisite for comparing human and chim-panzee responses to AIDS vaccines is a comprehen-sive assessment of which vaccines have beeninvolved in clinical trials to date. This was achievedby consulting the National Library of Medicine’sClinicalTrials.gov database (http://www.clinicaltri-als.gov/), for which registration of clinical trials hasbeen required for several years by the InternationalCommittee of Medical Journal Editors. The searchwas performed by using the operators ‘AIDS ORHIV’ (Disease or Condition field), and ‘Vaccine’(Experi mental Treatment field). It included all trialsthat were no longer recruiting patients. Thoughthis database may not constitute an exhaustiverepository of information regarding all trials of HIVvaccines to date, it currently describes around47,000 trials sponsored by the National Institutesof Health (NIH), other US federal agencies and pri-vate industry, conducted in 151 countries. For thepurposes of this investigation, it can be regarded asthe most complete source of HIV clinical trial datawhich is readily available. The International AIDSVaccine Initiative (IAVI) database (http://www.iavireport. org/trialsdb/default.asp) was also used toobtain vaccine details.
All the clinical trials located are summarised inTable 1. The 197 clinical trials of AIDS vaccines
registered involved 85 different vaccine products(strain specificity of recombinant proteins, forexample, was taken into account, meaning thatstrain MN recombinant gp120 was considered to bea separate vaccine from strain SF-2 recombinantgp120).
Figure 1 indicates the types and prevalence ofvaccines tested clinically in the 197 trials: 49 trials(25%) were of recombinant protein vaccines; 41 tri-als (21%) were of recombinant microbial vaccines(RMVs); and 50 trials (25%) used a combination oftwo or more approaches. These trials and the othersconstituting the remaining 29%, are discussedbelow.
Figure 2 provides a breakdown of the types ofvaccines in the RMV class. Of 41 trials, 13 (32%)involved canarypox vectors, closely followed by ade-novirus vectors (12 trials [29%]). Eight trials (20%)were based on vaccinia virus vaccines, and theremaining 19% involved a variety of viruses andbacteria, as detailed in the text.
Of the trials, 143 (72%) were Phase I trials(Figure 3), which involve a relatively small numberof volunteers (typically 20–100) over a two-yearperiod, in which humans encounter the vaccine forthe first time. Twenty-four (12%) were Phase II tri-als, in which vaccine candidates that appearedpromising in Phase I investigations are tested in upto 300 people, including those at high risk of HIVinfection or who are HIV-positive (HIV+). Sixteen(8%) Phase I/II trials were also registered (i.e.Phase I and Phase II trials performed in parallel).
Just seven of the 197 clinical trials progressed toPhase III (the final stage of testing prior to licens-
382 J. Bailey
Figure 1: AIDS vaccines in clinical trials
A total of 197 trials were registered with ClinicalTrials.gov, up to and including 11 November 2007. Mixed = combinations of two or more vaccines; inact. virus = inactivated virus vaccines; rec. protein = recombinantprotein vaccines; VLP = virus-like particles; DNA = DNA-based vaccines; RMVs = recombinant microbial vaccines;aut. cells = autologous cell vaccines.
mixed
perc
enta
ge
25
20
15
10
5
0inact.virus
rec.protein
peptide/lipopeptide
VLP DNA RMVs aut.cells
ing), in which the vaccine is tested typically in up to3000 people, involving individuals at higher risk. Afurther seven trials did not specify the phase.
Figure 4 summarises the status of the registeredtrials as of summer 2007. A total of 106 trials (54%)had reached an end, of which 95 trials (48% of thetotal) had been completed, with a further ten ter-minated and one suspended. Fifty-eight trials (29%)were ‘no longer recruiting’; 33 were either actively,or about to begin, recruiting (24 trials and nine tri-als, respectively).
Detailed Analysis and Human VersusChimpanzee Comparison
Vaccines and clinical trials were analysed in detailto assess whether those that failed in humans pro-vided protection from HIV infection and/or thera-peutic benefits in chimpanzees. A comprehensiveanalysis was performed of the recent history andcurrent situation surrounding vaccine developmentin chimpanzees (see Table 2 for trial information)and humans (Table 1), and to compare results andinformation from each species. Full use was made of the Nonhuman Primate HIV/SIV Vaccine Trials(NHPVT) Database (http://www.hiv.lanl.gov/content/vaccine/home.html). In these Tables, the interven-tions are shown in plain text, underlined, or boldtext, to indicate which specific vaccines were testedin both species (see Table legends).
Passive approaches
Many of the early experiments in HIV vaccineresearch centred on passively transferring HIV andSIV-specific antibodies from infected to non-infected animals, to see if this protected the recipi-ents from infection following a subsequent viralchallenge (for reviews, see 15–19). Five such trialsin chimpanzees are registered in the NHPVT data-base, and are summarised in Table 2.
The search of the ClinicalTrials.gov database didnot locate any human trials of passive antibodies toprotect against or to treat HIV infection, but manyreports of pre-clinical and clinical investigations ofpassive therapies for HIV/AIDS do exist. TheNHPVT database contains five entries for trials ofthis type, and all but the earliest (NHP .361; regis-tered in 1988) either prevented or controlled HIVinfection in chimpanzees (Table 2). Murthy et al.(17) referred to passive immunisation studies inchimpanzees involving a total of five different anti-bodies. Four of them were protective; the one thatwas not protective did, however, delay the onset ofinfection (20). HIV human hyperimmune immuno -globulin (HIVIG) had been shown to protect chim-panzees from HIV challenge when administeredboth pre- and post-exposure (21), an observationthat prompted the authors to conclude that induc-tion of humoral immunity was a pre-requisite forany HIV vaccine, but that cell-mediated immunitymay not be needed — a conclusion that is
Role of chimpanzees in AIDS vaccine research 383
Figure 2: RMV vaccines in clinical trials
Up to and including 11 November 2007, 41 trials involving recombinant microbial vectors were conducted, as identified by ClinicalTrials.gov. Multiple = combinations of two or more RMV vaccine types; AAV = adeno-associatedvirus; VEEA = Venezuelan Equine Encephalitis alphavirus; S. typhi = Salmonella typhi.
multiple
perc
enta
ge
35
30
25
20
15
10
5
0adenovirus AAV vaccinia canarypox VEEA S. typhi
unfounded in humans. Stiehm et al. (22), in con-trast, assessed the effects of HIVIG in 30 HIV+ chil-dren, where CD4 cell levels, plasma RNA copynumber, cellular virus load, immunoglobulin levels,and neutralising antibody titres were only mini-mally affected and clinical status was not changed.
A soluble CD4 analogue called ‘CD4-IgG’ (alsoknown as CD4 immunoadhesin, in which CD4 iscombined with an immunoglobulin for stability)was also protective in chimpanzee experiments(23). Trials in humans, however, suggested no evi-dence of clinical benefit: for example, a Phase I trialrevealed that CD4-IgG did not augment the effectsof the HIV inhibitor drug, azidothymidine (AZT;24), and a Phase I/II investigation revealed a slightimprovement of T-helper cell function, but no clini-cal benefit (25). Arguably, these difficulties may beexpected, because HIV+ individuals have high lev-els of soluble CD4 in their blood, even in quiteadvanced AIDS, suggesting it has little or no effecton progression of the disease.
More recently, Armbruster et al. (26, 27)described Phase I clinical trials of three humanmonoclonal antibodies (hMAbs), in which they weresafe and well tolerated. One of these antibodies hadbeen shown to delay seroconversion in chimpanzeessome time previously (16), and a paper reported aproof-of-principle human study (though the evi-dence is considered to be ‘circumstantial’; 28),showing that a cocktail of the same hMAbs could
delay viral rebound in HIV-infected patients whoseantiretroviral therapy has been interrupted. Therewere major caveats, however: the trial was neitherrandomised nor blinded; only two of eight chroni-cally infected patients showed rebound delay; theantibodies used had to be highly potent and used ata high dose; and, there was evidence of rapid escape.
Nevertheless, in spite of these caveats, it is claimedthat the findings from these experiments, in whichthe transferred antibodies protected chimpanzeesagainst HIV-1 infection when administered immedi-ately prior to or after viral challenge, directed the ini-tial push toward an HIV vaccine involvingrecombinant HIV envelope proteins to induce the pro-duction of HIV neutralising antibodies (29, 30). Thestatus of this approach to vaccine development is con-sidered in detail below (see ‘Recombinant Proteins’).
Attenuated/inactivated virus vaccines
Live attenuated virus vaccines have historicallybeen used with great success against many diseases(including measles, mumps and rubella), due totheir induction of strong and broadly reactivehumoral and cell-mediated immune responses (31).Despite this, putative AIDS vaccines of this classhave been limited to NHP studies and have notentered clinical trials (32, 33). This is due to con-cerns over reversion to virulence, recombinationwith other virions to form new, potentially highly-
Figure 3: Phases of AIDS vaccine clinicaltrials
Percentage of vaccine candidates in different phases ofclinical trials, as of 11 November 2007. Not classified = phase not specified. N = 197.
not classified
perc
enta
ge
35
30
25
20
15
10
5
0phase I phase II phase I/II phase III
Figure 4: Status of AIDS vaccine clinical trials
Summary of the status of registered clinical trials ofAIDS vaccines, as of 11 November 2007. R/NYR = trials recruiting or not yet recruiting; NLR = trials no longer recruiting; C/T/S = completed,terminated or suspended trials. N = 197.
R/NYR
perc
enta
ge
60
50
40
30
20
10
0NLR C/T/S
384 J. Bailey
pathogenic strains, and the dangerous conse-quences of integration of the attenuated virusgenetic material into the host genome (summarisedby Van der Ryst; 29). Although these concerns arelargely based on the results of macaque experi-ments, there are convincing human data: immuno-suppression has occurred in humans exposed toattenuated HIV via blood transfusions; and residualinfectivity caused over 200,000 people to be infectedby live polio virus during vaccination in the infa-mous Cutter incident (30).
Inactivated AIDS vaccines, however, have beentested clinically. Ten trials are registered, includingtwo in 2005 for the Remune vaccine (formerlyknown as HIV-1 Immunogen), which compriseswhole HIV particles that have been chemically andradioactively inactivated, with their envelopesremoved to preclude the infection of T-cells. Therationale is to use this vaccine as a therapeuticintervention, probably in tandem with anti-retrovi-ral drugs, in people already infected with HIV, inorder to control the activity of the virus by stimu-lating cell-mediated immunity and thus reduce therate of progression of AIDS.
However, Remune has failed to produce promisingresults in human subjects. Two of the ten trials (themost recent of which was registered in 2005) wereterminated, and a large Phase III study failed to findany additional benefit from Remune, when used toaugment anti-HIV drugs (10). Even more recently inJuly 2007, Remune’s manufacturer (ImmuneResponse Corporation) announced the discontinua-tion of its HIV Vaccine Development Program alto-gether, following a disappointing clinical trial ofRemune and its second-generation successor vaccine,IR103 (consisting of Remune and an adjuvant knownas Amplivax) (34). The results of human trials havetherefore prompted negative opinions concerning thisapproach in a number of reviews, for example,“…inactivated viruses have not been capable ofinducing adequate immunoresponse” (35).
There is evidence of enhanced immune responsein chimpanzees following vaccination with a gp120-depleted inactivated HIV-1 (36), and the NHPVTdatabase contained one record of a chimpanzee trialof this type of vaccine (Table 2). In 1993, inacti-vated whole HIV-1 was tested along with three dif-ferent adjuvants (37), in three groups of threechimpanzees — but even the group with the ‘best’immune responses became infected when chal-lenged shortly after their sixth immunisation. It istherefore assumed that vaccines of this type mayhave proceeded to clinical trials based on more-pos-itive results from experiments with other species.
Recombinant proteins
Immunogenic proteins have constituted a signifi-cant area of AIDS vaccine research, accounting for
49 (25%) of the 197 registered trials, though justseven of them have been registered since 2004.These 49 trials have tested just nine different vac-cines (or 15 vaccines, if similar proteins from differ-ent strains of HIV are included). Vaccines testedhave comprised the following: gp160 (expressed inVero cells [epithelial cells from African green mon-keys], in Sf9 cells by using recombinant bac-ulovirus, and from strains IIIB and LAI-2); gp120(strains SF2, MN, IIIB, A244 and W61D, and alsoEnv 2-3 [a yeast-derived gp120 combined with anadjuvant emulsion]); NefTat fusion protein; Tatprotein; EnvPro (an engineered and stabilised formof gp160 with adjuvant); and p24 protein (from thegag gene). Other proteins, such as the viral poly-merase and regulatory proteins Rev and Vpr, havealso been subject to evaluation. Perhaps the best-known candidate vaccines from this class are theAIDSVAX vaccines (AIDSVAX B/B and AIDSVAXB/E), each comprising two gp120 proteins from dif-ferent HIV clades.
The relatively high number of trials for the num-ber of recombinant protein vaccines is due to com-bination of the immunogenic proteins with avariety of adjuvants, as well as the testing of dif-ferent routes of administration. Notably, just nineof the total of 49 trials have not been completed. Ofthe 40 completed trials, just four had progressedbeyond Phase I. Of the nine trials that had notbeen completed, three were prematurely termi-nated. Almost all of the trials (45/49) involvedrecombinant envelope protein, since this protein isthe primary target for neutralising antibodies ininfected persons (38). Although invariablyimmunogenic, the antibodies induced have tendedto be very clade-specific and have failed to neu-tralise primary isolates of HIV derived from theblood of patients. Another major problem with theuse of stand-alone vaccines of this type was quicklyrevealed — they rarely induced the cell-mediatedarm of the immune system, which has beenregarded as an essential requirement for an HIVvaccine for some years (39).
Seven chimpanzee trials of recombinant pro-teins were listed in the NHPVT database, inwhich eight vaccines were tested (Table 2). Alleight tests showed the vaccines to be immuno-genic (though one test gave mixed results). Threeof the eight tests did not result in protection(involving two gp120 and one gp160 vaccine),whereas three tests did result in protection (all ofwhich involved gp120 vaccines). One of the tests(with a gp120 vaccine) gave mixed results (whereone animal was protected, but another was notprotected completely), and another test did notassess protection from infection.
Notable vaccines reported in the scientific litera-ture include recombinant gp120 vaccines that pro-tected chimpanzees from subsequent challenge(40–42), but that failed to show protection in
Role of chimpanzees in AIDS vaccine research 385
Tab
le 1
: C
linic
al t
rial
s o
f A
IDS
vacc
ines
lis
ted
in
th
e ClinicalTrials.gov
dat
abas
e
Dat
eP
reve
ntiv
e/re
g’d
Tri
al I
DO
ffic
ial t
itle
Inte
rven
tion
sP
hase
Sta
tus
ther
apeu
tic
Att
enu
ated
/in
acti
vate
d v
iru
s
1999
NC
T00
0009
43A
stu
dy t
o te
st if
giv
ing
Rem
une
(an
HIV
vac
cine
) ca
n im
prov
e th
e im
mun
e H
IV-1
imm
unog
en—
CT
syst
ems
of H
IV-p
osit
ive
pati
ents
who
are
als
o pa
rtic
ipat
ing
in A
CT
G 3
28
1999
NC
T00
0014
45P
hase
I s
tudy
to
eval
uate
the
saf
ety
and
imm
unog
enic
ity
of H
IV-1
imm
unog
en
HIV
-1 im
mun
ogen
(gp1
20-
IC
Tin
chi
ldre
n w
ith
HIV
-1 in
fect
ion
depl
eted
inac
tiva
ted
HIV
-1
prep
arat
ion
in I
ncom
plet
e F
reun
d’s
Adj
uvan
t (I
FA
)
1999
NC
T00
0021
72A
n ex
pand
ed a
cces
s, o
pen-
labe
l, co
mpa
ssio
nate
use
pro
toco
l of
Rem
une
in H
IV-
HIV
-1 im
mun
ogen
(Rem
une)
—C
T1-
infe
cted
adu
lts
wit
h C
D4
coun
t le
ss t
han
300
cells
/ml
1999
NC
T00
0021
73A
n ex
pand
ed a
cces
s, o
pen-
labe
l pro
toco
l of
Rem
une
(HIV
-1 im
mun
ogen
) in
HIV
-H
IV-1
imm
unog
en(R
emun
e)—
CT
1-in
fect
ed a
dult
s w
ith
CD
4 co
unt
550
cells
/ml a
nd g
reat
er
1999
NC
T00
0023
59A
mul
tice
ntre
, dou
ble-
blin
d, p
hase
III
, adj
uvan
t-co
ntro
lled
stud
y of
the
eff
ect
of
HIV
-1 im
mun
ogen
(Rem
une)
III
CT
10 u
nits
of
HIV
-1 im
mun
ogen
(R
emun
e) c
ompa
red
to I
FA
alo
ne e
very
12
wee
ks
on A
IDS-
free
sur
viva
l in
subj
ects
wit
h H
IV in
fect
ion
and
CD
4 T
-lym
phoc
ytes
be
twee
n 30
0 an
d 54
9 ce
lls/µ
l reg
ardl
ess
of c
onco
mit
ant
HIV
the
rapi
es
2000
NC
T00
0050
01A
pilo
t, p
hase
II,
dou
ble-
blin
d st
udy
to a
sses
s th
e vi
rolo
gic
effe
ct o
f R
emun
e H
IV-1
imm
unog
en(R
emun
e)II
CT
vers
usIF
A in
pat
ient
s w
ho a
re in
fect
ed w
ith
Hum
an I
mm
unod
efic
ienc
y V
irus
T
ype
1 (H
IV-1
), ha
ve a
pla
sma
HIV
-1 R
NA
leve
l les
s th
an 5
0 co
pies
/ml,
are
rece
ivin
g H
ighl
y A
ctiv
e A
ntir
etro
vira
l The
rapy
(H
AA
RT
), an
d w
ho s
ubse
quen
tly
disc
onti
nue
thei
r H
AA
RT
reg
imen
2000
NC
T00
0050
02A
ran
dom
ised
, dou
ble-
blin
d, a
djuv
ant-
cont
rolle
d, m
ulti
cent
re s
tudy
to
com
pare
R
emun
eII
IN
LR
Tth
e vi
rolo
gic
and
imm
unol
ogic
eff
ect
of H
AA
RT
plu
s R
emun
e ve
rsus
HA
AR
T
plus
(IF
A)
in a
ntir
etro
vira
l-naï
ve p
atie
nts
infe
cted
wit
h H
uman
Im
mun
odef
icie
ncy
Vir
us T
ype
1 (H
IV-1
)
2000
NC
T00
0061
53E
ffec
tive
ness
of
addi
ng R
emun
e to
the
cur
rent
ant
i-HIV
dru
g co
mbi
nati
onH
IV-1
imm
unog
en(R
emun
e)I
TT
2005
NC
T00
0217
62E
ffec
ts o
f im
mun
isat
ion
wit
h H
IV-1
imm
unog
en p
lus
anti
-HIV
tre
atm
ent
HIV
-1 im
mun
ogen
(Rem
une)
IIT
Tin
terr
upti
on o
n th
e le
vels
of
HIV
2005
NC
T00
2384
59Im
mun
opat
hoge
nesi
s of
acu
te a
nd e
arly
HIV
infe
ctio
n an
d th
e ro
le o
f H
IV-
HIV
-1 im
mun
ogen
—R
Tsp
ecif
ic C
D4
T-c
ell r
espo
nses
and
the
eff
ect
of t
heir
enh
ance
men
t by
pot
ent
anti
retr
ovir
al d
rugs
and
an
HIV
vac
cine
386 J. Bailey
Role of chimpanzees in AIDS vaccine research 387
Tab
le 1
: co
nti
nu
ed
Dat
eP
reve
ntiv
e/re
g’d
Tri
al I
DO
ffic
ial t
itle
Inte
rven
tion
sP
hase
Sta
tus
ther
apeu
tic
Rec
omb
inan
t p
rote
in
1999
NC
T00
0006
32A
pha
se I
clin
ical
tri
al t
o ev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y of
100µg
of
Env
2-3
IC
PE
nv 2
-3 in
MF
59
1999
NC
T00
0006
33A
pha
se I
mul
tice
ntre
clin
ical
tri
al t
o ev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y gp
160
vacc
ine
IC
Tof
Im
mun
o-A
G r
ecom
bina
nt H
IV g
p160
in a
sym
ptom
atic
HIV
ser
opos
itiv
e (I
mm
un
o-A
G)
indi
vidu
als
1999
NC
T00
0006
67A
pha
se I
/II
dose
esc
alat
ion
stud
y of
intr
ader
mal
gp1
60 t
o ev
alua
te s
afet
y,
gp16
0 va
ccin
eI
CT
dela
yed
type
hyp
erse
nsit
ivit
y (s
kin
test
) re
spon
ses
and
imm
unog
enic
ity
in
(Mic
roG
eneS
ys)
asym
ptom
atic
HIV
ser
opos
itiv
e pa
tien
ts w
ith
mor
e th
an 4
00 C
D4+
cells
1999
NC
T00
0007
45A
pha
se I
mul
tice
ntre
, ran
dom
ised
, dou
ble-
blin
d, p
lace
bo-c
ontr
olle
d tr
ial t
o gp
160
vacc
ine
IC
Pev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y of
HIV
-1 r
ecom
bina
nt e
nvel
ope
(Mic
roG
eneS
ys)
glyc
opro
tein
gp1
60
1999
NC
T00
0007
49A
pha
se I
clin
ical
tri
al t
o ev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y of
200µg
of
rgp
120/
HIV
-1 S
F-2
IC
Pgp
120
(CH
O)
BIO
CIN
E in
MF
59 e
mul
sion
ver
sus
the
emul
sion
con
trol
: thr
ee
inje
ctio
ns a
t 0,
1, a
nd 6
mon
ths
1999
NC
T00
0007
55A
pha
se I
/II
tria
l of
vacc
ine
ther
apy
of H
IV-1
infe
cted
indi
vidu
als
wit
h 50
–500
rg
p12
0/H
IV-1
MN
IC
TC
D4
cells
/mm
3
1999
NC
T00
0007
57A
pha
se I
mul
tice
ntre
tri
al t
o ev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y of
HIV
-1
gp16
0 va
ccin
eI
CP
reco
mbi
nant
env
elop
e gl
ycop
rote
in g
p160
(Mic
roG
eneS
ys)
1999
NC
T00
0007
62A
pla
cebo
-con
trol
led,
pha
se I
clin
ical
tri
al t
o ev
alua
te t
he s
afet
y an
d rg
p12
0/H
IV-1
MN
IC
Tim
mun
ogen
icit
y of
rec
ombi
nant
env
elop
e pr
otei
ns o
f H
IV-1
gp1
60 a
nd g
p120
in
rgp
120/
HIV
-1 S
F-2
child
ren
≥1
mon
th o
ld w
ith
asym
ptom
atic
HIV
infe
ctio
ngp
160
vacc
ine
(Mic
roG
eneS
ys)
Dat
a w
ere
cons
ider
ed, u
p to
and
inc
ludi
ng 1
1 N
ovem
ber
2007
. Rec
ords
of A
IDS
vac
cine
cli
nica
l tri
als
retr
ieve
d fr
om h
ttp:
//ww
w.c
linic
altr
ials
.gov
. A s
earc
h w
as p
erfo
rmed
by
usin
g th
e op
erat
ors
‘AID
S O
R H
IV’ i
n th
e D
isea
se o
r C
ondi
tion
fiel
d an
d ‘v
acci
ne’ i
n th
e E
xper
imen
tal T
reat
men
tfi
eld,
and
it i
nclu
ded
all t
rial
s th
at w
ere
no lo
nger
rec
ruit
ing
pati
ents
. Thi
s se
arch
pro
duce
d 19
7 re
sult
s, d
etai
ling
cli
nica
l tri
als
invo
lvin
g 85
dif
fere
nt v
acci
ne p
rodu
cts
(str
ain
spec
ific
ity
of r
ecom
bina
nt p
rote
ins,
for
exam
ple,
was
take
n in
toac
coun
t, m
eani
ng s
trai
n M
N r
ecom
bina
nt g
p120
was
con
side
red
a se
para
te v
acci
ne fr
om s
trai
n S
F-2
rec
ombi
nant
gp1
20).
The
dat
e th
e tr
ial w
as r
egis
tere
d is
not
nec
essa
rily
the
date
the
tria
l com
men
ced;
whe
re b
oth
date
s ar
e kn
own,
thes
e ar
e gi
ven,
wit
h th
e ea
rlie
st b
eing
199
9 w
hen
the
data
base
was
ini
tiat
ed, t
houg
h tr
ials
may
hav
e be
gun
prio
r to
this
date
(com
p. =
[tri
al] c
ompl
eted
). F
or tr
ial s
tatu
s, C
= C
ompl
eted
, T =
Ter
min
ated
, S =
Sus
pend
ed, N
LR
= N
o L
onge
r R
ecru
itin
g, N
YR
= N
ot Y
et R
ecru
itin
g, R
= R
ecru
itin
g.T
he fi
nal c
olum
n in
dica
tes
whe
ther
the
vacc
ine
was
pri
mar
ily
prev
enti
ve (P
) or
ther
apeu
tic
(T).
Inte
rven
tion
s ar
e sh
own
in p
lain
text
, und
erli
ned,
or
bold
text
, to
indi
cate
whi
chva
ccin
es w
ere
prev
ious
ly te
sted
in
chim
panz
ees,
giv
en th
e ca
veat
that
the
freq
uent
poo
r qu
alit
y of
vac
cine
inf
orm
atio
n re
quir
es th
is to
be
an e
duca
ted
gues
s: P
lain
text
= n
o ev
i-de
nce
foun
d fo
r pr
ior
test
ing
in c
him
panz
ees;
Und
erli
ned
text
= s
imil
ar b
ut n
ot i
dent
ical
to v
acci
ne te
sted
in
chim
panz
ees
(e.g
. sam
e pl
asm
id c
onta
inin
g sa
me
HIV
gen
e am
ong
othe
r ge
nes;
dif
fere
nt a
djuv
ant;
etc.
); B
old
text
= i
dent
ical
vac
cine
test
ed i
n ch
impa
nzee
s.
388 J. BaileyTa
ble
1:
con
tin
ued
Dat
eP
reve
ntiv
e/re
g’d
Tri
al I
DO
ffic
ial t
itle
Inte
rven
tion
sP
hase
Sta
tus
ther
apeu
tic
1999
NC
T00
0007
74A
pha
se I
stu
dy t
o ev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y of
rec
ombi
nant
rg
p12
0/H
IV-1
MN
IN
LR
P/T
HIV
-1 e
nvel
ope
anti
gen
in c
hild
ren
born
to
HIV
-infe
cted
mot
hers
rgp
120/
HIV
-1 S
F-2
1999
NC
T00
0007
77A
ctiv
e im
mun
isat
ion
of H
IV-1
infe
cted
, pre
gnan
t w
omen
wit
h C
D4
lym
phoc
yte
gp16
0 va
ccin
eI
CP
/Tco
unts
≥40
0/m
m3 :
A p
hase
I s
tudy
of
safe
ty a
nd im
mun
ogen
icit
y of
Vax
Syn
(Mic
roG
eneS
ys)
reco
mbi
nant
gp1
60 (
Not
e: s
ome
pati
ents
rec
eive
pla
cebo
)
1999
NC
T00
0007
79A
pha
se I
com
para
tive
blin
ded
tria
l of
seve
ral H
IV-1
der
ived
imm
unog
ens
in
rgp
120/
HIV
-1II
IBI
CT
infe
cted
indi
vidu
als
wit
h ≥
500
CD
4 ce
lls/m
m3
rgp
120/
HIV
-1M
Nrg
p12
0/H
IV-1
SF
-2E
nv 2
-3
1999
NC
T00
0007
82A
pha
se I
/II
stud
y of
Del
ayed
-Typ
e H
yper
sens
itiv
ity
(DT
H)
reac
tion
s to
gp
160
vacc
ine
IC
Tin
trad
erm
al H
IV e
nvel
ope
anti
gen
(Im
mu
no-
AG
)gp
160
vacc
ine
(Mic
roG
eneS
ys)
1999
NC
T00
0008
09Sa
fety
and
eff
ecti
vene
ss o
f tw
o di
ffer
ent
form
ulat
ions
of
an H
IV v
acci
ne in
M
N r
sgp1
20/H
IV-1
IT
Tin
fant
s bo
rn t
o H
IV-in
fect
ed w
omen
1999
NC
T00
0008
22A
pha
se I
/II
doub
le-b
lind
cont
rolle
d tr
ial t
o de
term
ine
the
safe
ty a
nd im
mun
o-gp
160
vacc
ine
IC
Tge
nici
ty o
f H
IV-1
MN
rgp
160
Imm
uno-
AG
vac
cine
the
rapy
in H
IV-in
fect
ed
(Im
mu
no-
AG
)in
divi
dual
s w
ith
≥50
0/m
m3
CD
4+T
-cel
ls a
nd 2
00–4
00/m
m3
CD
4+T
-cel
ls
1999
NC
T00
0008
32A
ran
dom
ised
, pla
cebo
-con
trol
led,
dou
ble-
blin
ded
phas
e I
safe
ty a
nd
rgp
120/
HIV
-1 S
F-2
IC
Pim
mun
ogen
icit
y tr
ial o
f re
com
bina
nt e
nvel
ope
prot
ein,
HIV
-1 S
F-2
rgp
120
(BIO
CIN
E),
com
bine
d w
ith
MF
59 in
HIV
-1 u
ninf
ecte
d ad
ult
volu
ntee
rs
1999
NC
T00
0008
53A
pha
se I
, mul
tice
ntre
, ran
dom
ised
, dou
ble-
blin
d, p
lace
bo-c
ontr
olle
d H
IV-1
rg
p12
0/H
IV-1
MN
IC
Pva
ccin
e tr
ial t
o ev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y of
low
dos
e M
N
rsgp
120/
HIV
-1 (
Gen
ente
ch)
in c
ombi
nati
on w
ith
QS2
1 ad
juva
nt o
r al
um in
he
alth
y ad
ults
1999
NC
T00
0009
56A
pha
se I
mul
tice
ntre
tri
al t
o ev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y of
HIV
-1
gp16
0 va
ccin
eI
CP
reco
mbi
nant
env
elop
e gl
ycop
rote
in g
p160
(Mic
roG
eneS
ys)
1999
NC
T00
0009
57A
pha
se I
mul
tice
ntre
clin
ical
tri
al t
o ev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y gp
160
vacc
ine
IC
Pof
vac
cini
a de
rive
d H
IV-1
rec
ombi
nant
env
elop
e gl
ycop
rote
in (
gp16
0) o
f(I
mm
un
o-A
G)
Hum
an I
mm
unod
efic
ienc
y V
irus
: Eva
luat
ion
of a
ccel
erat
ed s
ched
ules
Role of chimpanzees in AIDS vaccine research 389
Tab
le 1
: co
nti
nu
ed
Dat
eP
reve
ntiv
e/re
g’d
Tri
al I
DO
ffic
ial t
itle
Inte
rven
tion
sP
hase
Sta
tus
ther
apeu
tic
1999
NC
T00
0009
58A
pla
cebo
-con
trol
led,
pha
se I
, pilo
t cl
inic
al t
rial
to
eval
uate
the
saf
ety
and
imm
unog
enic
ity
of E
nv 2
-3, a
yea
st-d
eriv
ed r
ecom
bina
nt e
nvel
ope
prot
ein
of
HIV
-1, i
n co
mbi
nati
on w
ith
MT
P-P
E/M
F59
in in
divi
dual
s w
ith
HIV
infe
ctio
n E
nv 2
-3I
CT
(pla
cebo
pat
ient
s re
ceiv
e M
F59
em
ulsi
on o
nly)
1999
NC
T00
0009
68A
pha
se I
mul
tice
ntre
clin
ical
tri
al t
o ev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y of
gp
160
vacc
ine
IC
Pva
ccin
ia-d
eriv
ed H
IV-1
rec
ombi
nant
env
elop
e gl
ycop
rote
in (
gp16
0)(I
mm
un
o-A
G)
1999
NC
T00
0009
72A
pha
se I
clin
ical
tri
al t
o ev
alua
te:
Env
2-3
IC
PP
art
A. T
he s
afet
y of
MT
P-P
E/M
F59
adj
uvan
t em
ulsi
on
Par
t B
. The
saf
ety
and
imm
unog
enic
ity
of E
nv 2
-3, a
yea
st-d
eriv
ed r
ecom
bina
nt
enve
lope
pro
tein
of
HIV
-1, i
n co
mbi
nati
on w
ith
MT
P-P
E/M
F59
1999
NC
T00
0009
77A
ctiv
e im
mun
isat
ion
of a
sym
ptom
atic
, HIV
-infe
cted
indi
vidu
als
wit
h gp
160
vacc
ine
IC
Tre
com
bina
nt g
p160
HIV
-1 a
ntig
en: A
pha
se I
/II
stud
y of
imm
unog
enic
ity
and
(Mic
roG
eneS
ys)
toxi
city
1999
NC
T00
0010
19Sa
fety
of
and
imm
une
resp
onse
to
an H
IV v
acci
ne (
SF-2
gp1
20)
wit
h or
wit
hout
rg
p12
0/H
IV-1
SF
-2I
CP
MT
P-P
E/M
F59
adj
uvan
t
1999
NC
T00
0010
20A
pha
se I
stu
dy o
f th
e sa
fety
and
imm
unog
enic
ity
of r
gp12
0/H
IV-1
IIIB
vac
cine
rg
p12
0/H
IV-1
IIIB
IC
Pin
hea
lthy
adu
lt s
ubje
cts
(Not
e: s
tudy
ext
ende
d on
ly f
or s
ubje
cts
who
hav
e rg
p12
0/H
IV-1
MN
prev
ious
ly r
ecei
ved
rgp1
20/H
IV-1
IIIB
or
rgp1
20/H
IV-1
MN
on
VE
U 0
06 o
r V
EU
006
rol
love
r st
udy)
1999
NC
T00
0010
21A
pha
se I
mul
tice
ntre
stu
dy o
f th
e sa
fety
and
imm
unog
enic
ity
of M
N
rgp
120/
HIV
-1II
IBI
CP
rgp1
20/H
IV-1
vac
cine
giv
en e
ithe
r al
one
or in
com
bina
tion
wit
h II
IB
rgp
120/
HIV
-1M
Nrg
p120
/HIV
-1 v
acci
ne in
hea
lthy
adu
lt s
ubje
cts
(Not
e: o
rigi
nal s
tudy
ext
ende
d on
ly f
or p
atie
nts
prev
ious
ly e
nrol
led
on V
EU
009
)
Dat
a w
ere
cons
ider
ed, u
p to
and
inc
ludi
ng 1
1 N
ovem
ber
2007
. Rec
ords
of A
IDS
vac
cine
cli
nica
l tri
als
retr
ieve
d fr
om h
ttp:
//ww
w.c
linic
altr
ials
.gov
. A s
earc
h w
as p
erfo
rmed
by
usin
g th
e op
erat
ors
‘AID
S O
R H
IV’ i
n th
e D
isea
se o
r C
ondi
tion
fiel
d an
d ‘v
acci
ne’ i
n th
e E
xper
imen
tal T
reat
men
tfi
eld,
and
it i
nclu
ded
all t
rial
s th
at w
ere
no lo
nger
rec
ruit
ing
pati
ents
. Thi
s se
arch
pro
duce
d 19
7 re
sult
s, d
etai
ling
cli
nica
l tri
als
invo
lvin
g 85
dif
fere
nt v
acci
ne p
rodu
cts
(str
ain
spec
ific
ity
of r
ecom
bina
nt p
rote
ins,
for
exam
ple,
was
take
n in
toac
coun
t, m
eani
ng s
trai
n M
N r
ecom
bina
nt g
p120
was
con
side
red
a se
para
te v
acci
ne fr
om s
trai
n S
F-2
rec
ombi
nant
gp1
20).
The
dat
e th
e tr
ial w
as r
egis
tere
d is
not
nec
essa
rily
the
date
the
tria
l com
men
ced;
whe
re b
oth
date
s ar
e kn
own,
thes
e ar
e gi
ven,
wit
h th
e ea
rlie
st b
eing
199
9 w
hen
the
data
base
was
ini
tiat
ed, t
houg
h tr
ials
may
hav
e be
gun
prio
r to
this
date
(com
p. =
[tri
al] c
ompl
eted
). F
or tr
ial s
tatu
s, C
= C
ompl
eted
, T =
Ter
min
ated
, S =
Sus
pend
ed, N
LR
= N
o L
onge
r R
ecru
itin
g, N
YR
= N
ot Y
et R
ecru
itin
g, R
= R
ecru
itin
g.T
he fi
nal c
olum
n in
dica
tes
whe
ther
the
vacc
ine
was
pri
mar
ily
prev
enti
ve (P
) or
ther
apeu
tic
(T).
Inte
rven
tion
s ar
e sh
own
in p
lain
text
, und
erli
ned,
or
bold
text
, to
indi
cate
whi
chva
ccin
es w
ere
prev
ious
ly te
sted
in
chim
panz
ees,
giv
en th
e ca
veat
that
the
freq
uent
poo
r qu
alit
y of
vac
cine
inf
orm
atio
n re
quir
es th
is to
be
an e
duca
ted
gues
s: P
lain
text
= n
o ev
i-de
nce
foun
d fo
r pr
ior
test
ing
in c
him
panz
ees;
Und
erli
ned
text
= s
imil
ar b
ut n
ot i
dent
ical
to v
acci
ne te
sted
in
chim
panz
ees
(e.g
. sam
e pl
asm
id c
onta
inin
g sa
me
HIV
gen
e am
ong
othe
r ge
nes;
dif
fere
nt a
djuv
ant;
etc.
); B
old
text
= i
dent
ical
vac
cine
test
ed i
n ch
impa
nzee
s.
390 J. BaileyTa
ble
1:
con
tin
ued
Dat
eP
reve
ntiv
e/re
g’d
Tri
al I
DO
ffic
ial t
itle
Inte
rven
tion
sP
hase
Sta
tus
ther
apeu
tic
1999
NC
T00
0010
31A
pha
se I
I cl
inic
al t
rial
to
eval
uate
the
imm
unog
enic
ity
and
reac
toge
nici
ty o
f rg
p12
0/H
IV-1
MN
IIC
Pth
e re
com
bina
nt H
IV-1
env
elop
e va
ccin
es S
F-2
rgp
120
(CH
O)
[Chi
ron
vacc
ines
] rg
p12
0/H
IV-1
SF
-2in
MF
59 a
djuv
ant
and
MN
rgp
120/
HIV
-1 [
Vax
Gen
] in
alu
m a
djuv
ant
in h
ealt
hy
adul
ts
1999
NC
T00
0010
37A
pha
se I
, mul
tice
ntre
, clin
ical
tri
al t
o ev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y gp
160
vacc
ine
IC
Pof
vac
cini
a-de
rive
d M
N H
IV-1
rec
ombi
nant
env
elop
e gl
ycop
rote
in (
rgp1
60)
of
(Im
mu
no-
AG
)H
IV a
t tw
o di
ffer
ent
vacc
inat
ion
sche
dule
s
1999
NC
T00
0010
41A
ctiv
e im
mun
isat
ion
of H
IV-1
infe
cted
, pre
gnan
t w
omen
wit
h C
D4
lym
phoc
yte
rgp
120/
HIV
-1M
NI
CT
coun
ts ≥
400/
mm
3 : A
pha
se I
stu
dy o
f sa
fety
and
imm
unog
enic
ity
of M
N
rgp1
20/H
IV-1
vac
cine
(N
ote:
som
e pa
tien
ts r
ecei
ve p
lace
bo)
1999
NC
T00
0010
42A
pha
se I
, ran
dom
ised
, dou
ble-
blin
d, p
lace
bo-c
ontr
olle
d, c
linic
al t
rial
to
com
pare
rg
p12
0/H
IV-1
SF
-2I
CP
the
safe
ty a
nd im
mun
ogen
icit
y of
rec
ombi
nant
env
elop
e pr
otei
n rg
p120
/HIV
-1SF
2 (B
IOC
INE
) co
mbi
ned
wit
h se
ven
adju
vant
s in
hea
lthy
HIV
-1
unin
fect
ed in
divi
dual
s
1999
NC
T00
0010
43A
pha
se I
, mul
tice
ntre
, ran
dom
ised
tri
al t
o ev
alua
te t
he s
afet
y an
d gp
160
vacc
ine
IC
Pim
mun
ogen
icit
y of
vac
cini
a-de
rive
d M
N H
IV-1
rec
ombi
nant
env
elop
e (I
mm
un
o-A
G)
glyc
opro
tein
(rg
p160
) of
hum
an im
mun
odef
icie
ncy
viru
s at
tw
o di
ffer
ent
vacc
inat
ion
sche
dule
s
1999
NC
T00
0010
44A
pha
se I
, mul
tice
ntre
, ran
dom
ised
, dou
ble-
blin
d, p
lace
bo-c
ontr
olle
d H
IV-1
rg
p12
0/H
IV-1
MN
IC
Pva
ccin
e tr
ial t
o ev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y of
rgp
120/
HIV
-1M
N
(Gen
ente
ch)
in c
ombi
nati
on w
ith
QS2
1 ad
juva
nt a
nd/o
r al
um in
hea
lthy
adu
lts
1999
NC
T00
0010
46A
ctiv
e im
mun
isat
ion
of H
IV-in
fect
ed p
regn
ant
wom
en: A
pha
se I
stu
dy o
f sa
fety
rg
p12
0/H
IV-1
SF
-2I
TT
and
imm
unog
enic
ity
of a
rgp
120/
HIV
-1 v
acci
ne (
Not
e: s
ome
pati
ents
rec
eive
pl
aceb
o)
1999
NC
T00
0010
52A
pha
se I
, mul
tice
ntre
, ran
dom
ised
, dou
ble-
blin
d, p
lace
bo-c
ontr
olle
d H
IV-1
rg
p12
0/H
IV-1
MN
IC
Pva
ccin
e tr
ial t
o ev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y of
MN
rec
ombi
nant
so
lubl
e gp
120/
HIV
-1 (
rsgp
120/
HIV
-1)
(Gen
ente
ch)
in c
ombi
nati
on w
ith
QS2
1 ad
juva
nt a
nd/o
r al
um in
hea
lthy
adu
lts
1999
NC
T00
0010
56A
pha
se I
mul
tice
ntre
clin
ical
tri
al t
o ev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y gp
160
vacc
ine
IC
Pof
vac
cini
a-de
rive
d H
IV-1
rec
ombi
nant
env
elop
e gl
ycop
rote
in (
gp16
0) o
f hu
man
(I
mm
un
o-A
G)
imm
unod
efic
ienc
y vi
rus:
Eva
luat
ion
of a
200µg
dos
e
Role of chimpanzees in AIDS vaccine research 391
Tab
le 1
: co
nti
nu
ed
Dat
eP
reve
ntiv
e/re
g’d
Tri
al I
DO
ffic
ial t
itle
Inte
rven
tion
sP
hase
Sta
tus
ther
apeu
tic
1999
NC
T00
0010
96A
pha
se I
, mul
tice
ntre
, ran
dom
ised
, dou
ble-
blin
d, p
lace
bo-c
ontr
olle
d tr
ial t
o M
N r
gp12
0/H
IV-1
and
IN
LR
Pev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y of
HIV
-1 M
N r
sgp1
20 a
nd b
ival
ent
A24
4 rg
p120
/HIV
-1A
IDSV
AX
B/E
(H
IV-1
MN
rgp
120/
A24
4 rg
p120
) in
com
bina
tion
wit
h Q
S-21
rg
p12
0/H
IV-1
MN
wit
h or
wit
hout
alu
m in
hea
lthy
HIV
-1 u
ninf
ecte
d ad
ults
1999
NC
T00
0019
92A
pha
se I
stu
dy o
f th
e sa
fety
and
imm
unog
enic
ity
of r
gp12
0/H
IV-1
IIIB
vac
cine
rg
p12
0/H
IV-1
IIIB
IC
Pin
HIV
-1 s
erop
osit
ive
adul
t vo
lunt
eers
1999
NC
T00
0022
04A
pha
se I
, obs
erve
r-bl
ind,
pla
cebo
-con
trol
led
stud
y of
the
chi
ron
vacc
ine
HIV
H
IV p
24/M
F59
IC
Pp2
4/M
F59
adm
inis
tere
d to
hea
lthy
HIV
-ser
oneg
ativ
e ad
ults
1999
NC
T00
0024
02A
pha
se I
/II
tria
l to
eval
uate
the
saf
ety
and
imm
unog
enic
ity
of A
IDSV
AX
B/B
and
A
IDS
VA
X B
/B a
nd
I/
IIC
PB
/E v
acci
nes
in t
he U
SAA
IDS
VA
X B
/E (
MN
rg
p12
0/H
IV-1
an
d G
NE
8 rg
p12
0/H
IV-1
) an
d (
MN
rg
p12
0/H
IV-1
an
d A
244
rgp
120/
HIV
-1)
1999
NC
T00
0024
41A
pha
se I
II t
rial
to
dete
rmin
e th
e ef
fica
cy o
f bi
vale
nt A
IDSV
AX
B/B
vac
cine
in
AID
SV
AX
B/B
(M
N
III
CP
adul
ts a
t ri
sk o
f se
xual
ly t
rans
mit
ted
HIV
-1 in
fect
ion
in N
orth
Am
eric
arg
p12
0/H
IV-1
an
d G
NE
8 rg
p12
0/H
IV-1
)
2000
NC
T00
0063
27A
pha
se I
II t
rial
to
dete
rmin
e th
e ef
fica
cy o
f A
IDSV
AX
B/E
vac
cine
in
AID
SV
AX
B/E
(M
N
III
CP
intr
aven
ous
drug
use
rs in
Ban
gkok
, Tha
iland
rgp
120/
HIV
-1 a
nd
A24
4 rg
p12
0/H
IV-1
)
2001
NC
T00
0273
65A
n in
vest
igat
iona
l com
bina
tion
vac
cine
giv
en t
o pe
ople
who
are
not
infe
cted
C
ombi
nati
on v
acci
ne
IN
LR
Pw
ith
HIV
(Nef
Tat
and
gp1
20 W
61D
)N
efT
atgp
120
W61
D
Dat
a w
ere
cons
ider
ed, u
p to
and
inc
ludi
ng 1
1 N
ovem
ber
2007
. Rec
ords
of A
IDS
vac
cine
cli
nica
l tri
als
retr
ieve
d fr
om h
ttp:
//ww
w.c
linic
altr
ials
.gov
. A s
earc
h w
as p
erfo
rmed
by
usin
g th
e op
erat
ors
‘AID
S O
R H
IV’ i
n th
e D
isea
se o
r C
ondi
tion
fiel
d an
d ‘v
acci
ne’ i
n th
e E
xper
imen
tal T
reat
men
tfi
eld,
and
it i
nclu
ded
all t
rial
s th
at w
ere
no lo
nger
rec
ruit
ing
pati
ents
. Thi
s se
arch
pro
duce
d 19
7 re
sult
s, d
etai
ling
cli
nica
l tri
als
invo
lvin
g 85
dif
fere
nt v
acci
ne p
rodu
cts
(str
ain
spec
ific
ity
of r
ecom
bina
nt p
rote
ins,
for
exam
ple,
was
take
n in
toac
coun
t, m
eani
ng s
trai
n M
N r
ecom
bina
nt g
p120
was
con
side
red
a se
para
te v
acci
ne fr
om s
trai
n S
F-2
rec
ombi
nant
gp1
20).
The
dat
e th
e tr
ial w
as r
egis
tere
d is
not
nec
essa
rily
the
date
the
tria
l com
men
ced;
whe
re b
oth
date
s ar
e kn
own,
thes
e ar
e gi
ven,
wit
h th
e ea
rlie
st b
eing
199
9 w
hen
the
data
base
was
ini
tiat
ed, t
houg
h tr
ials
may
hav
e be
gun
prio
r to
this
date
(com
p. =
[tri
al] c
ompl
eted
). F
or tr
ial s
tatu
s, C
= C
ompl
eted
, T =
Ter
min
ated
, S =
Sus
pend
ed, N
LR
= N
o L
onge
r R
ecru
itin
g, N
YR
= N
ot Y
et R
ecru
itin
g, R
= R
ecru
itin
g.T
he fi
nal c
olum
n in
dica
tes
whe
ther
the
vacc
ine
was
pri
mar
ily
prev
enti
ve (P
) or
ther
apeu
tic
(T).
Inte
rven
tion
s ar
e sh
own
in p
lain
text
, und
erli
ned,
or
bold
text
, to
indi
cate
whi
chva
ccin
es w
ere
prev
ious
ly te
sted
in
chim
panz
ees,
giv
en th
e ca
veat
that
the
freq
uent
poo
r qu
alit
y of
vac
cine
inf
orm
atio
n re
quir
es th
is to
be
an e
duca
ted
gues
s: P
lain
text
= n
o ev
i-de
nce
foun
d fo
r pr
ior
test
ing
in c
him
panz
ees;
Und
erli
ned
text
= s
imil
ar b
ut n
ot i
dent
ical
to v
acci
ne te
sted
in
chim
panz
ees
(e.g
. sam
e pl
asm
id c
onta
inin
g sa
me
HIV
gen
e am
ong
othe
r ge
nes;
dif
fere
nt a
djuv
ant;
etc.
); B
old
text
= i
dent
ical
vac
cine
test
ed i
n ch
impa
nzee
s.
392 J. BaileyTa
ble
1:
con
tin
ued
Dat
eP
reve
ntiv
e/re
g’d
Tri
al I
DO
ffic
ial t
itle
Inte
rven
tion
sP
hase
Sta
tus
ther
apeu
tic
2002
NC
T00
0311
09T
he e
ffec
tive
ness
of
hum
an a
ntib
odie
s in
infl
uenc
ing
an A
IDS-
like
dise
ase
in
gp16
0 M
N/L
AI-
2—
NL
RP
mon
keys
2004
NC
T00
0769
47Sa
fety
of
the
Env
Pro
HIV
vac
cine
in h
ealt
hy v
olun
teer
sE
nvP
roI
CP
2005
NC
T00
1174
29A
pha
se I
, ran
dom
ised
, dou
ble-
blin
d cl
inic
al t
rial
of
the
HIV
gp1
20/N
efT
at/
HIV
gp1
20/N
efT
at/A
S02A
I
RT
AS0
2A v
acci
ne c
andi
date
in s
ubje
cts
wit
h w
ell-c
ontr
olle
d ch
roni
c H
IV-1
va
ccin
ein
fect
ion
on H
AA
RT
2005
NC
T00
1225
64P
hase
I s
tudy
eva
luat
ing
the
syst
emic
and
muc
osal
saf
ety
and
imm
unog
enic
ity
HIV
-1 g
p16
0I
TP
(com
p.
of a
rec
ombi
nant
HIV
-1 g
p160
(M
N/L
AI)
adm
inis
tere
d by
tra
nsm
ucos
al (
nasa
l 20
03)
or v
agin
al)
rout
es, a
lone
or
form
ulat
ed w
ith
DC
-Cho
l, in
HIV
neg
ativ
e vo
lunt
eers
(A
NR
S V
AC
14)
2006
NC
T00
3690
31A
pha
se I
, ope
n-la
bel,
para
llel g
roup
tri
al t
o ev
alua
te s
afet
y an
d im
mun
ogen
icit
y H
uman
Im
mun
odef
icie
ncy
IN
LR
Pof
thr
ee n
asal
imm
unis
atio
ns u
sing
a f
ixed
dos
e-le
vel o
f H
IV g
p140
V2
loop
Vir
us g
lyco
prot
ein
140
dele
ted
prot
ein
adju
vant
ed w
ith
LT
K63
fol
low
ed b
y in
tram
uscu
lar
boos
ting
wit
h (v
acci
ne)
HIV
gp1
40 V
2 lo
op d
elet
ed p
rote
in a
djuv
ante
d w
ith
MF
59 w
hen
adm
inis
tere
d to
hea
lthy
adu
lts
2006
NC
T00
4124
77A
pha
se I
stu
dy o
f sa
fety
and
imm
unog
enic
ity
of t
he W
RA
IR H
IV-1
vac
cine
H
IV L
Fn-
p24
IC
PL
Fn-
p24
adm
inis
tere
d by
the
intr
amus
cula
r (I
M)
rout
e in
hea
lthy
adu
lts
2007
NC
T00
5054
01A
pha
se I
saf
ety
and
imm
unog
enic
ity
tria
l of
reco
mbi
nant
HIV
-1 t
at in
HIV
-1
Rec
ombi
nant
HIV
-1 T
at
IC
Tin
fect
ed a
dult
vol
unte
ers
prot
ein
2007
NC
T00
5296
98A
pha
se I
saf
ety
and
imm
unog
enic
ity
tria
l of
reco
mbi
nant
HIV
-1 t
at p
rote
in in
B
iolo
gica
lly a
ctiv
e I
CP
(com
p.
HIV
-1 u
ninf
ecte
d ad
ult
volu
ntee
rsre
com
bina
nt T
at p
rote
in20
04)
(ISS
P-0
01)
Pep
tid
e/L
ipop
epti
de
1999
NC
T00
0007
75A
pha
se I
saf
ety
and
imm
unog
enic
ity
tria
l of
UB
I Sy
nVac
(H
IV-1
MN
oct
amer
ic
rgp
120/
HIV
-1M
NI
CP
V3
pept
ide
vacc
ine)
Mon
oval
ent
octa
mer
ic V
3pe
ptid
e va
ccin
e
1999
NC
T00
0007
95A
pha
se I
saf
ety
and
imm
unog
enic
ity
tria
l of
UB
I m
ulti
vale
nt H
IV-1
pep
tide
H
IV-1
pep
tide
imm
unog
en,
IC
Pim
mun
ogen
in H
IV-1
ser
oneg
ativ
e hu
man
sub
ject
sm
ulti
vale
nt
Role of chimpanzees in AIDS vaccine research 393
Tab
le 1
: co
nti
nu
ed
Dat
eP
reve
ntiv
e/re
g’d
Tri
al I
DO
ffic
ial t
itle
Inte
rven
tion
sP
hase
Sta
tus
ther
apeu
tic
1999
NC
T00
0007
98A
pha
se I
saf
ety
and
imm
unog
enic
ity
tria
l of
UB
I m
icro
part
icul
ate
mon
oval
ent
HIV
-1 p
epti
de v
acci
ne,
IC
PH
IV-1
MN
pep
tide
imm
unog
en in
HIV
-1 s
eron
egat
ive
hum
an s
ubje
cts
mic
ropa
rtic
ulat
e m
onov
alen
t
1999
NC
T00
0008
45A
pha
se I
saf
ety
and
imm
unog
enic
ity
tria
l of
UB
I H
IV li
pope
ptid
e va
ccin
e P
3C54
1b li
pope
ptid
eI
CP
com
pone
nt P
3C54
1b in
HIV
-1 s
eron
egat
ive
hum
an s
ubje
cts
1999
NC
T00
0008
46A
pha
se I
tri
al t
o ev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y of
the
UB
I H
IV-1
MN
H
IV-1
pep
tide
vac
cine
,I
CP
PN
D p
epti
de im
mun
ogen
, giv
en b
y IM
inje
ctio
n, in
com
bina
tion
wit
h th
e U
BI
mic
ropa
rtic
ulat
e m
onov
alen
tm
icro
part
icul
ate
mon
oval
ent
HIV
-1 M
N b
ranc
hed
pept
ide
give
n or
ally
, in
HIV
-1 p
epti
de im
mun
ogen
,H
IV-1
uni
nfec
ted
volu
ntee
rsm
ulti
vale
nt
1999
NC
T00
0008
86A
pha
se I
saf
ety
and
imm
unog
enic
ity
tria
l of
HIV
-1 g
p120
C4-
V3
hybr
id
HIV
-1 C
4-V
3 po
lyva
lent
IC
Ppo
lyva
lent
pep
tide
imm
unog
en m
ixed
in m
iner
al o
il co
ntai
ning
man
nose
pe
ptid
e va
ccin
em
ono-
olea
te (
IFA
)
1999
NC
T00
0010
60A
pha
se I
tri
al o
f H
IV-1
C4-
V3
poly
vale
nt p
epti
de v
acci
ne in
HIV
-1 in
fect
ed
HIV
-1 C
4-V
3 po
lyva
lent
IC
Tpe
rson
spe
ptid
e va
ccin
e
1999
NC
T00
0013
86P
hase
I p
roto
col f
or t
he e
valu
atio
n of
the
saf
ety
and
imm
unog
enic
ity
of
PC
LU
S 3-
18 M
NI
CT
vacc
inat
ion
wit
h sy
nthe
tic
HIV
env
elop
e pe
ptid
es in
pat
ient
s w
ith
earl
y hu
man
P
CL
US
6.1
MN
imm
unod
efic
ienc
y vi
rus
infe
ctio
n
1999
NC
T00
0023
53A
pha
se I
saf
ety
and
imm
unog
enic
ity
tria
l of
UB
I H
IV li
pope
ptid
e P
3C54
1b li
pope
ptid
eI
CT
imm
unot
hera
peut
ic P
3C54
1b in
HIV
-1 s
erop
osit
ive
hum
an s
ubje
cts
2000
NC
T00
0057
79Sa
fety
of
the
cand
idat
e va
ccin
e C
4-V
3 al
one
or w
ith
inte
rleu
kin-
12 (
IL-1
2) in
H
IV-1
C4-
V3
poly
vale
ntI
CT
HIV
-infe
cted
pat
ient
s re
ceiv
ing
effe
ctiv
e an
ti-H
IV d
rug
ther
apy
pept
ide
vacc
ine
2004
NC
T00
0760
37Sa
fety
of
and
imm
une
resp
onse
to
a ne
w H
IV C
TL
ME
PH
IV C
TL
ME
PI
NL
RP
Dat
a w
ere
cons
ider
ed, u
p to
and
inc
ludi
ng 1
1 N
ovem
ber
2007
. Rec
ords
of A
IDS
vac
cine
cli
nica
l tri
als
retr
ieve
d fr
om h
ttp:
//ww
w.c
linic
altr
ials
.gov
. A s
earc
h w
as p
erfo
rmed
by
usin
g th
e op
erat
ors
‘AID
S O
R H
IV’ i
n th
e D
isea
se o
r C
ondi
tion
fiel
d an
d ‘v
acci
ne’ i
n th
e E
xper
imen
tal T
reat
men
tfi
eld,
and
it i
nclu
ded
all t
rial
s th
at w
ere
no lo
nger
rec
ruit
ing
pati
ents
. Thi
s se
arch
pro
duce
d 19
7 re
sult
s, d
etai
ling
cli
nica
l tri
als
invo
lvin
g 85
dif
fere
nt v
acci
ne p
rodu
cts
(str
ain
spec
ific
ity
of r
ecom
bina
nt p
rote
ins,
for
exam
ple,
was
take
n in
toac
coun
t, m
eani
ng s
trai
n M
N r
ecom
bina
nt g
p120
was
con
side
red
a se
para
te v
acci
ne fr
om s
trai
n S
F-2
rec
ombi
nant
gp1
20).
The
dat
e th
e tr
ial w
as r
egis
tere
d is
not
nec
essa
rily
the
date
the
tria
l com
men
ced;
whe
re b
oth
date
s ar
e kn
own,
thes
e ar
e gi
ven,
wit
h th
e ea
rlie
st b
eing
199
9 w
hen
the
data
base
was
ini
tiat
ed, t
houg
h tr
ials
may
hav
e be
gun
prio
r to
this
date
(com
p. =
[tri
al] c
ompl
eted
). F
or tr
ial s
tatu
s, C
= C
ompl
eted
, T =
Ter
min
ated
, S =
Sus
pend
ed, N
LR
= N
o L
onge
r R
ecru
itin
g, N
YR
= N
ot Y
et R
ecru
itin
g, R
= R
ecru
itin
g.T
he fi
nal c
olum
n in
dica
tes
whe
ther
the
vacc
ine
was
pri
mar
ily
prev
enti
ve (P
) or
ther
apeu
tic
(T).
Inte
rven
tion
s ar
e sh
own
in p
lain
text
, und
erli
ned,
or
bold
text
, to
indi
cate
whi
chva
ccin
es w
ere
prev
ious
ly te
sted
in
chim
panz
ees,
giv
en th
e ca
veat
that
the
freq
uent
poo
r qu
alit
y of
vac
cine
inf
orm
atio
n re
quir
es th
is to
be
an e
duca
ted
gues
s: P
lain
text
= n
o ev
i-de
nce
foun
d fo
r pr
ior
test
ing
in c
him
panz
ees;
Und
erli
ned
text
= s
imil
ar b
ut n
ot i
dent
ical
to v
acci
ne te
sted
in
chim
panz
ees
(e.g
. sam
e pl
asm
id c
onta
inin
g sa
me
HIV
gen
e am
ong
othe
r ge
nes;
dif
fere
nt a
djuv
ant;
etc.
); B
old
text
= i
dent
ical
vac
cine
test
ed i
n ch
impa
nzee
s.
394 J. BaileyTa
ble
1:
con
tin
ued
Dat
eP
reve
ntiv
e/re
g’d
Tri
al I
DO
ffic
ial t
itle
Inte
rven
tion
sP
hase
Sta
tus
ther
apeu
tic
2005
NC
T00
1217
58R
ando
mis
ed d
oubl
e-bl
inde
d ph
ase
II A
IDS
vacc
ine
stud
y co
mpa
ring
L
IPO
-5II
NL
RP
imm
unog
enic
ity
and
safe
ty o
f 3
dose
s of
lipo
pept
ide
(LIP
O-5
) ve
rsus
plac
ebo
in
non-
infe
cted
HIV
vol
unte
ers
(AN
RS
VA
C 1
8)
2005
NC
T00
1952
34A
pha
se I
mul
tice
ntre
, ran
dom
ised
, dou
ble-
blin
d, p
lace
bo-c
ontr
olle
d tr
ial t
o H
IV C
TL
ME
PI
CT
eval
uate
the
saf
ety
and
imm
unog
enic
ity
of a
n H
IV C
TL
mul
ti-e
pito
pe p
epti
de
vacc
ine
form
ulat
ed w
ith
RC
529-
SE a
nd G
M-C
SF g
iven
to
HIV
-1 p
osit
ive
adul
ts
on s
tabl
e H
AA
RT
2006
NC
T00
3818
75A
pilo
t st
udy
to in
vest
igat
e th
e sa
fety
and
imm
unog
enic
ity
of a
pep
tide
vac
cine
E
1M18
4V p
epti
de v
acci
neI
RT
for
HIV
infe
cted
HL
A-A
2 in
divi
dual
s de
sign
ed t
o im
pede
the
dev
elop
men
t of
an
tire
trov
iral
res
ista
nce
Vir
us-
lik
e p
arti
cles
1999
NC
T00
0008
35A
mul
tice
ntre
, ran
dom
ised
, pla
cebo
-con
trol
led,
dou
ble-
blin
d tr
ial t
o ev
alua
te
HIV
-1 p
seud
ovir
ion
vacc
ine
IT
Pth
e sa
fety
and
imm
unog
enic
ity
of a
n H
IV-1
pse
udov
irio
n va
ccin
e
1999
NC
T00
0010
53A
pha
se I
saf
ety
and
imm
unog
enic
ity
stud
y of
HIV
p17
/p24
:Ty-
VL
P in
HIV
-1
HIV
p17
/p24
:Ty-
VL
PI
CP
sero
nega
tive
sub
ject
s
DN
A v
acci
nes
1999
NC
T00
0010
88A
pha
se I
saf
ety
and
imm
unog
enic
ity
tria
l of
the
faci
litat
ed H
IV-1
Gag
-Pol
DN
A
AP
L 4
00-0
47I
NL
RP
vacc
ine
(AP
L-4
00-0
47, A
pollo
n, I
nc.)
give
n in
tram
uscu
larl
y by
nee
dle
and
syri
nge
or B
ioje
ctor
200
0 ne
edle
-fre
e je
t in
ject
ion
syst
em in
HIV
-1 u
ninf
ecte
d ad
ult
volu
ntee
rs
1999
NC
T00
0015
38A
pha
se I
stu
dy o
f A
PL
400
-003
, a c
andi
date
HIV
vac
cine
, in
HIV
-neg
ativ
e A
PL
400
-003
IC
Pvo
lunt
eers
1999
NC
T00
0022
31G
EN
EV
AX
-HIV
(A
PL
400
-003
), a
cand
idat
e D
NA
vac
cine
: A p
ilot
dose
esc
alat
ion
GE
NE
VA
X-H
IVI
CP
stud
y of
GE
NE
VA
X-H
IV d
eliv
ered
intr
amus
cula
rly
usin
g th
e B
ioje
ctor
200
0 in
(A
PL
400
-003
)H
IV s
eron
egat
ive
volu
ntee
rs
1999
NC
T00
0022
32G
EN
EV
AX
-HIV
(A
PL
400
-003
), a
cand
idat
e D
NA
vac
cine
: A p
ilot
stud
y of
G
EN
EV
AX
-HIV
IC
PG
EN
EV
AX
-HIV
giv
en b
y in
tram
uscu
lar
or in
trad
erm
al a
dmin
istr
atio
n in
HIV
(A
PL
400
-003
)se
rone
gati
ve v
olun
teer
s
Role of chimpanzees in AIDS vaccine research 395
Tab
le 1
: co
nti
nu
ed
Dat
eP
reve
ntiv
e/re
g’d
Tri
al I
DO
ffic
ial t
itle
Inte
rven
tion
sP
hase
Sta
tus
ther
apeu
tic
1999
NC
T00
0023
50A
pha
se I
tri
al o
f A
PL
400
-003
vac
cine
: Saf
ety
and
imm
une
resp
onse
eva
luat
ions
A
PL
400
-003
IC
Pof
mul
tipl
e in
ject
ions
at
esca
lati
ng d
oses
in a
sym
ptom
atic
HIV
infe
cted
pat
ient
s
2001
NC
T00
0096
85H
IV-1
vac
cine
tes
t in
uni
nfec
ted
adul
t vo
lunt
eers
VR
C43
02I
CP
2002
NC
T00
0435
11Sa
fety
of
an H
IV D
NA
vac
cine
giv
en t
o H
IV u
ninf
ecte
d ad
ults
pGA
2/JS
2I
CP
2002
NC
T00
0458
38H
IV-1
vac
cine
tes
t in
uni
nfec
ted
adul
t vo
lunt
eers
VR
C-H
IVD
NA
006-
00-V
PI
CP
2002
NC
T00
0479
31A
pha
se I
clin
ical
tri
al t
o ev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y of
a m
ulti
clad
e V
RC
-HIV
DN
A00
9-00
-VP
IN
LR
PH
IV-1
DN
A p
lasm
id v
acci
ne, V
RC
-HIV
DN
A00
9-00
-VP
, in
unin
fect
ed a
dult
vo
lunt
eers
2003
NC
T00
0521
82Sa
fety
of
and
imm
une
syst
em r
espo
nse
to a
n H
IV v
acci
ne (
EP
HIV
-109
0) in
E
P H
IV-1
090
IC
TH
IV in
fect
ed p
atie
nts
2003
NC
T00
0548
60Sa
fety
of
and
imm
une
syst
em r
espo
nse
to a
n H
IV v
acci
ne (
EP
HIV
-109
0) in
E
P H
IV-1
090
IC
PH
IV u
ninf
ecte
d ad
ults
2003
NC
T00
0690
30A
pha
se I
clin
ical
tri
al t
o ev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y of
the
HIV
-1
DN
A v
acci
ne V
RC
-HIV
DN
A00
9-00
-VP
(G
ag-P
ol-N
ef-m
ulti
clad
e E
nv)
wit
h th
e V
RC
-HIV
DN
A00
9-00
-VP
IN
LR
Ppl
asm
id c
ytok
ine
adju
vant
VR
C-A
DJD
NA
004-
IL2-
VP
(IL
-2/I
g)(G
ag-P
ol-N
ef-m
ulti
clad
e E
nv)
2003
NC
T00
0718
51Sa
fety
of
and
imm
une
resp
onse
to
an H
IV-1
DN
A v
acci
ne (
VR
C
VR
C-H
IVD
NA
009-
00-V
PI/
IIC
PH
IVD
NA
009-
00-V
P)
in H
IV u
ninf
ecte
d ad
ults
2004
NC
T00
0895
31C
andi
date
HIV
vac
cine
VR
C-H
IVD
NA
016-
00-V
PI
NL
RP
Dat
a w
ere
cons
ider
ed, u
p to
and
inc
ludi
ng 1
1 N
ovem
ber
2007
. Rec
ords
of A
IDS
vac
cine
cli
nica
l tri
als
retr
ieve
d fr
om h
ttp:
//ww
w.c
linic
altr
ials
.gov
. A s
earc
h w
as p
erfo
rmed
by
usin
g th
e op
erat
ors
‘AID
S O
R H
IV’ i
n th
e D
isea
se o
r C
ondi
tion
fiel
d an
d ‘v
acci
ne’ i
n th
e E
xper
imen
tal T
reat
men
tfi
eld,
and
it i
nclu
ded
all t
rial
s th
at w
ere
no lo
nger
rec
ruit
ing
pati
ents
. Thi
s se
arch
pro
duce
d 19
7 re
sult
s, d
etai
ling
cli
nica
l tri
als
invo
lvin
g 85
dif
fere
nt v
acci
ne p
rodu
cts
(str
ain
spec
ific
ity
of r
ecom
bina
nt p
rote
ins,
for
exam
ple,
was
take
n in
toac
coun
t, m
eani
ng s
trai
n M
N r
ecom
bina
nt g
p120
was
con
side
red
a se
para
te v
acci
ne fr
om s
trai
n S
F-2
rec
ombi
nant
gp1
20).
The
dat
e th
e tr
ial w
as r
egis
tere
d is
not
nec
essa
rily
the
date
the
tria
l com
men
ced;
whe
re b
oth
date
s ar
e kn
own,
thes
e ar
e gi
ven,
wit
h th
e ea
rlie
st b
eing
199
9 w
hen
the
data
base
was
ini
tiat
ed, t
houg
h tr
ials
may
hav
e be
gun
prio
r to
this
date
(com
p. =
[tri
al] c
ompl
eted
). F
or tr
ial s
tatu
s, C
= C
ompl
eted
, T =
Ter
min
ated
, S =
Sus
pend
ed, N
LR
= N
o L
onge
r R
ecru
itin
g, N
YR
= N
ot Y
et R
ecru
itin
g, R
= R
ecru
itin
g.T
he fi
nal c
olum
n in
dica
tes
whe
ther
the
vacc
ine
was
pri
mar
ily
prev
enti
ve (P
) or
ther
apeu
tic
(T).
Inte
rven
tion
s ar
e sh
own
in p
lain
text
, und
erli
ned,
or
bold
text
, to
indi
cate
whi
chva
ccin
es w
ere
prev
ious
ly te
sted
in
chim
panz
ees,
giv
en th
e ca
veat
that
the
freq
uent
poo
r qu
alit
y of
vac
cine
inf
orm
atio
n re
quir
es th
is to
be
an e
duca
ted
gues
s: P
lain
text
= n
o ev
i-de
nce
foun
d fo
r pr
ior
test
ing
in c
him
panz
ees;
Und
erli
ned
text
= s
imil
ar b
ut n
ot i
dent
ical
to v
acci
ne te
sted
in
chim
panz
ees
(e.g
. sam
e pl
asm
id c
onta
inin
g sa
me
HIV
gen
e am
ong
othe
r ge
nes;
dif
fere
nt a
djuv
ant;
etc.
); B
old
text
= i
dent
ical
vac
cine
test
ed i
n ch
impa
nzee
s.
396 J. BaileyTa
ble
1:
con
tin
ued
Dat
eP
reve
ntiv
e/re
g’d
Tri
al I
DO
ffic
ial t
itle
Inte
rven
tion
sP
hase
Sta
tus
ther
apeu
tic
2005
NC
T00
1116
05A
pha
se I
clin
ical
tri
al t
o ev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y of
an
HIV
-1
HIV
-1 g
ag D
NA
IN
LR
Pga
gD
NA
vac
cine
wit
h or
wit
hout
IL
-12
DN
A a
djuv
ant,
boo
sted
wit
h ho
mol
ogou
s pl
asm
ids
in h
ealt
hy, H
IV-1
uni
nfec
ted
adul
t pa
rtic
ipan
ts
2005
NC
T00
1159
60A
pha
se I
clin
ical
tri
al t
o ev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y of
HIV
-1 g
agH
IV-1
gag
DN
AI
RP
DN
A v
acci
ne a
lone
or
wit
h IL
-15
DN
A, b
oost
ed w
ith
HIV
-1 g
agD
NA
+ I
L-1
5 D
NA
or
HIV
-1 g
agD
NA
+ I
L-1
2 D
NA
, in
heal
thy,
HIV
-1 u
ninf
ecte
d ad
ult
part
icip
ants
2005
NC
T00
1250
99Sa
fety
of
and
imm
une
resp
onse
to
a D
NA
HIV
vac
cine
(V
RC
-HIV
DN
A00
9-00
-VP
) V
RC
-HIV
DN
A00
9-00
-VP
I/II
NL
RT
in H
IV in
fect
ed in
divi
dual
s w
ith
acut
e H
IV in
fect
ion
2005
NC
T00
1410
24Sa
fety
of
and
imm
une
resp
onse
to
the
expe
rim
enta
l pre
vent
ive
HIV
vac
cine
, E
P H
IV-1
090
IN
LR
PE
P H
IV-1
090,
in h
ealt
hy, H
IV-1
uni
nfec
ted
adul
ts
2005
NC
T00
1871
48E
valu
atio
n of
the
tol
erab
ility
and
saf
ety
of a
rec
ombi
nant
HIV
-1 m
ulti
-env
elop
e E
nvD
NA
IN
LR
PD
NA
pla
smid
vac
cine
(E
nvD
NA
) in
hea
lthy
adu
lts
2005
NC
T00
1953
12A
pha
se I
mul
tice
ntre
, ran
dom
ised
, dou
ble-
blin
d, p
lace
bo-c
ontr
olle
d tr
ial t
o H
IV-1
gag
DN
AI
TT
eval
uate
the
saf
ety
and
imm
unog
enic
ity
of a
n H
IV-1
gag
DN
A v
acci
ne
adm
inis
tere
d al
one
or w
ith
esca
lati
ng d
oses
of
IL-1
2 D
NA
or
IL-1
5 D
NA
m
olec
ular
adj
uvan
ts t
o H
IV-1
pos
itiv
e ad
ults
rec
eivi
ng s
tabl
e H
AA
RT
2005
NC
T00
2491
06A
ran
dom
ised
, pla
cebo
-con
trol
led,
dos
e-es
cala
ting
, dou
ble-
blin
ded
phas
e I
stud
y A
DV
AX
e/g
IN
LR
P(c
omp
.to
eva
luat
e th
e sa
fety
and
imm
unog
enic
ity
of a
cla
de C
DN
A v
acci
ne A
DV
AX
e/g
A
DV
AX
p/n
-t (
AD
VA
X)
2003
)+
AD
VA
X p
/n-t
(A
DV
AX
) ad
min
iste
red
intr
amus
cula
rly
to H
IV u
ninf
ecte
d,
heal
thy
volu
ntee
rs
2005
NC
T00
2702
05A
pha
se I
/II,
ran
dom
ised
, dou
ble-
blin
d st
udy
to e
valu
ate
the
safe
ty, t
oler
abili
ty,
LC
002
I/II
RT
and
imm
unog
enic
ity
of L
C00
2, a
Der
maV
ir v
acci
ne, i
n H
IV-1
infe
cted
sub
ject
s cu
rren
tly
unde
r tr
eatm
ent
wit
h H
AA
RT
2007
NC
T00
5284
89A
pha
se I
clin
ical
tri
al t
o ev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y of
PE
NN
VA
X-B
P
ennV
ax B
(Gag
, Pol
, Env
)I
NY
RP
(Gag
, Pol
, Env
) gi
ven
alon
e, w
ith
IL-1
2 D
NA
, or
wit
h a
dose
esc
alat
ion
of I
L-1
5 D
NA
, in
heal
thy,
HIV
-1 u
ninf
ecte
d ad
ult
part
icip
ants
2007
NC
T00
5329
74A
pha
se I
saf
ety
and
imm
unog
enic
ity
stud
y of
the
Pha
rmex
a-E
pim
mun
e H
IV-1
C
TL
epi
tope
-bas
ed D
NA
vac
cine
(E
P H
IV-1
090)
adm
inis
tere
d us
ing
a B
ioje
ctor
E
P10
90I
RT
2000
nee
dle-
free
imm
unis
atio
n de
vice
in H
IV-1
infe
cted
indi
vidu
als
rece
ivin
g po
tent
Com
bina
tion
Ant
iret
rovi
ral T
hera
py
Role of chimpanzees in AIDS vaccine research 397
Tab
le 1
: co
nti
nu
ed
Dat
eP
reve
ntiv
e/re
g’d
Tri
al I
DO
ffic
ial t
itle
Inte
rven
tion
sP
hase
Sta
tus
ther
apeu
tic
2007
NC
T00
5459
87E
valu
atio
n of
loca
l and
sys
tem
ic r
eact
ogen
icit
y fo
llow
ing
seri
al a
dmin
istr
atio
n of
A
DV
AX
-EP
IR
P
AD
VA
X, a
cla
de C
DN
A v
acci
ne, A
DV
AX
e/g
+ A
DV
AX
p/n
-t, b
y Ic
hor
Tri
Gri
d™
in v
ivo
elec
trop
orat
ion
to H
IV u
ninf
ecte
d, h
ealt
hy v
olun
teer
s
Rec
omb
inan
t m
icro
bia
l va
ccin
es
Ade
novi
rus
2004
NC
T00
0801
06E
ffec
tive
ness
of
and
imm
une
resp
onse
to
HIV
vac
cina
tion
fol
low
ed b
y tr
eatm
ent
MR
K A
d5 H
IV-1
gag
IIN
LR
Tin
terr
upti
on in
HIV
infe
cted
pat
ient
s
2004
NC
T00
0833
30A
pha
se I
clin
ical
tri
al t
o ev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y of
a r
ecom
bina
nt
VR
C-H
IVA
DV
014-
00-V
PI
NL
RP
mul
ticl
ade
HIV
-1 a
deno
vira
l vec
tor
vacc
ine,
VR
C-H
IVA
DV
014-
00-V
P, i
n un
infe
cted
adu
lt v
olun
teer
s
2004
NC
T00
0914
16Sa
fety
of
and
imm
une
resp
onse
to
an H
IV-1
vac
cine
boo
st
VR
C-H
IVA
DV
014-
00-V
PI
NL
RP
(VR
C-H
IVA
DV
014-
00-V
P)
in H
IV u
ninf
ecte
d ad
ults
who
par
tici
pate
d in
HV
TN
052
2004
NC
T00
0955
76In
vest
igat
ion
of V
520
in a
n H
IV v
acci
ne p
roof
-of-
conc
ept
stud
yV
520
IIT
P
2005
NC
T00
1020
89A
pha
se I
clin
ical
tri
al t
o ev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y of
a b
oost
er d
ose
VR
C-H
IVA
DV
014-
00-V
PI
CP
of a
rec
ombi
nant
mul
ticl
ade
HIV
-1 a
deno
vira
l vec
tor
vacc
ine,
V
RC
-HIV
AD
V01
4-00
-VP
VR
C-H
IVA
DV
014-
00-V
P, i
n un
infe
cted
sub
ject
s w
ho w
ere
prev
ious
ly im
mun
ised
bo
oste
rw
ith
VR
C-H
IVD
NA
009-
00-V
P in
VR
C 0
04
2005
NC
T00
1086
54A
pha
se I
clin
ical
tri
al t
o ev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y of
a b
oost
er
VR
C-H
IVA
DV
014-
00-V
PI
NL
RP
dose
of
a re
com
bina
nt m
ulti
clad
e H
IV-1
ade
novi
ral v
ecto
r va
ccin
e,
VR
C-H
IVA
DV
014-
00-V
P, i
n un
infe
cted
sub
ject
s w
ho w
ere
prev
ious
ly im
mun
ised
w
ith
VR
C-H
IVD
NA
016-
00-V
P in
VR
C 0
0
2005
NC
T00
1198
73Sa
fety
of
and
imm
une
resp
onse
to
an e
xper
imen
tal H
IV v
acci
ne
VR
C-H
IVA
DV
014-
00-V
PI
NL
RP
(VR
C-H
IVA
DV
014-
00-V
P)
in H
IV u
ninf
ecte
d ad
ults
Dat
a w
ere
cons
ider
ed, u
p to
and
inc
ludi
ng 1
1 N
ovem
ber
2007
. Rec
ords
of A
IDS
vac
cine
cli
nica
l tri
als
retr
ieve
d fr
om h
ttp:
//ww
w.c
linic
altr
ials
.gov
. A s
earc
h w
as p
erfo
rmed
by
usin
g th
e op
erat
ors
‘AID
S O
R H
IV’ i
n th
e D
isea
se o
r C
ondi
tion
fiel
d an
d ‘v
acci
ne’ i
n th
e E
xper
imen
tal T
reat
men
tfi
eld,
and
it i
nclu
ded
all t
rial
s th
at w
ere
no lo
nger
rec
ruit
ing
pati
ents
. Thi
s se
arch
pro
duce
d 19
7 re
sult
s, d
etai
ling
cli
nica
l tri
als
invo
lvin
g 85
dif
fere
nt v
acci
ne p
rodu
cts
(str
ain
spec
ific
ity
of r
ecom
bina
nt p
rote
ins,
for
exam
ple,
was
take
n in
toac
coun
t, m
eani
ng s
trai
n M
N r
ecom
bina
nt g
p120
was
con
side
red
a se
para
te v
acci
ne fr
om s
trai
n S
F-2
rec
ombi
nant
gp1
20).
The
dat
e th
e tr
ial w
as r
egis
tere
d is
not
nec
essa
rily
the
date
the
tria
l com
men
ced;
whe
re b
oth
date
s ar
e kn
own,
thes
e ar
e gi
ven,
wit
h th
e ea
rlie
st b
eing
199
9 w
hen
the
data
base
was
ini
tiat
ed, t
houg
h tr
ials
may
hav
e be
gun
prio
r to
this
date
(com
p. =
[tri
al] c
ompl
eted
). F
or tr
ial s
tatu
s, C
= C
ompl
eted
, T =
Ter
min
ated
, S =
Sus
pend
ed, N
LR
= N
o L
onge
r R
ecru
itin
g, N
YR
= N
ot Y
et R
ecru
itin
g, R
= R
ecru
itin
g.T
he fi
nal c
olum
n in
dica
tes
whe
ther
the
vacc
ine
was
pri
mar
ily
prev
enti
ve (P
) or
ther
apeu
tic
(T).
Inte
rven
tion
s ar
e sh
own
in p
lain
text
, und
erli
ned,
or
bold
text
, to
indi
cate
whi
chva
ccin
es w
ere
prev
ious
ly te
sted
in
chim
panz
ees,
giv
en th
e ca
veat
that
the
freq
uent
poo
r qu
alit
y of
vac
cine
inf
orm
atio
n re
quir
es th
is to
be
an e
duca
ted
gues
s: P
lain
text
= n
o ev
i-de
nce
foun
d fo
r pr
ior
test
ing
in c
him
panz
ees;
Und
erli
ned
text
= s
imil
ar b
ut n
ot i
dent
ical
to v
acci
ne te
sted
in
chim
panz
ees
(e.g
. sam
e pl
asm
id c
onta
inin
g sa
me
HIV
gen
e am
ong
othe
r ge
nes;
dif
fere
nt a
djuv
ant;
etc.
); B
old
text
= i
dent
ical
vac
cine
test
ed i
n ch
impa
nzee
s.
398 J. BaileyTa
ble
1:
con
tin
ued
Dat
eP
reve
ntiv
e/re
g’d
Tri
al I
DO
ffic
ial t
itle
Inte
rven
tion
sP
hase
Sta
tus
ther
apeu
tic
2005
NC
T00
1832
61A
ran
dom
ised
pha
se I
I st
udy
of t
hera
peut
ic im
mun
isat
ion
and
trea
tmen
t M
RK
Ad5
HIV
-1 g
ag/p
ol/n
efII
NL
RT
inte
rrup
tion
am
ong
subj
ects
who
beg
an p
oten
t an
tire
trov
iral
the
rapy
wit
hin
30
days
of
diag
nosi
s of
acu
te o
r re
cent
HIV
infe
ctio
n
2006
NC
T00
3506
23In
vest
igat
ion
of V
520
in a
HIV
vac
cine
dos
e re
fine
men
t st
udy
V52
0II
TP
2006
NC
T00
4137
25A
mul
tice
ntre
dou
ble-
blin
d ra
ndom
ised
pla
cebo
-con
trol
led
phas
e II
B t
est-
of-
MR
KA
d5 H
IV-1
gag
/pol
/nef
IIS
Pco
ncep
t st
udy
to e
valu
ate
the
safe
ty a
nd e
ffic
acy
of a
thr
ee-d
ose
regi
men
of
the
clad
e B
-bas
ed M
erck
ade
novi
rus
sero
type
5 H
IV-1
gag
/pol
/nef
vac
cine
in H
IV-1
un
infe
cted
adu
lts
in S
outh
Afr
ica
2007
NC
T00
4799
99V
RC
012
: A p
hase
I c
linic
al t
rial
of
the
safe
ty a
nd im
mun
ogen
icit
y of
an
HIV
-1
VR
C-H
IVA
DV
027-
00-V
PI
RP
aden
ovir
al v
ecto
r se
roty
pe 3
5 do
se e
scal
atio
n as
a s
ingl
e ag
ent
and
prim
e–bo
ost
VR
C-H
IVA
DV
038-
00-V
Psc
hedu
les
wit
h an
HIV
-1 a
deno
vira
l vec
tor
sero
type
5 v
acci
ne in
uni
nfec
ted
adul
ts
2007
NC
T00
4864
08A
pha
se I
B o
pen-
labe
l clin
ical
tri
al t
o ex
pand
the
cha
ract
eris
atio
n of
the
M
RK
Ad5
HIV
-1 g
ag/p
ol/n
efI
SP
imm
une
resp
onse
s to
the
Mer
ck a
deno
viru
s se
roty
pe 5
HIV
-1 g
ag/p
ol/n
ef v
acci
ne
in h
ealt
hy, H
IV-1
uni
nfec
ted
adul
t pa
rtic
ipan
ts
Rec
omb
inan
t m
icro
bia
l va
ccin
es
Ade
no-a
ssoc
iate
d vi
rus
2007
NC
T00
4820
27A
pha
se I
ran
dom
ised
, pla
cebo
-con
trol
led,
dou
ble-
blin
d do
se-e
scal
atio
n tr
ial t
o tg
AA
C09
IC
P(c
omp
.ev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y of
tgA
AC
09, a
gag
-PR
-RT
AA
V H
IV
2003
)va
ccin
e
Rec
omb
inan
t m
icro
bia
l va
ccin
es
Vac
cini
a
1999
NC
T00
0007
67A
mul
tice
ntre
, ran
dom
ised
, pla
cebo
-con
trol
led,
dou
ble-
blin
d tr
ial t
o ev
alua
te t
he
TB
C-3
B v
acci
neI
CP
safe
ty a
nd im
mun
ogen
icit
y of
a r
ecom
bina
nt v
acci
nia-
HIV
-1 I
IIB
env
/gag
/pol
va
ccin
e (T
BC
-3B
)
2003
NC
T00
0519
22D
evel
opm
ent
of a
new
HIV
vac
cine
Pol
yEnv
1I
NL
RP
2005
NC
T00
1870
44E
valu
atio
n of
the
saf
ety
of a
pol
yval
ent
vacc
inia
vir
us-H
IV-1
env
elop
e P
olyE
nv1
IN
LR
Pre
com
bina
nt v
acci
ne (
Pol
yEnv
1) in
hea
lthy
adu
lts
2005
NC
T00
1899
30A
sin
gle-
blin
d, r
ando
mis
ed, c
ontr
olle
d, p
hase
II
stud
y to
eva
luat
e im
mun
ogen
icit
y M
VA
-nef
IIN
LR
T
and
safe
ty o
f tw
o do
ses
of t
he M
VA
-nef
HIV
vac
cine
in H
IV-1
infe
cted
pat
ient
s M
VA
-BN
wit
h C
D4
> 2
50/µ
l
Role of chimpanzees in AIDS vaccine research 399
Tab
le 1
: co
nti
nu
ed
Dat
eP
reve
ntiv
e/re
g’d
Tri
al I
DO
ffic
ial t
itle
Inte
rven
tion
sP
hase
Sta
tus
ther
apeu
tic
2005
NC
T00
2521
48A
ran
dom
ised
, pla
cebo
-con
trol
led,
dos
e-es
cala
ting
, dou
ble-
blin
ded
phas
e I
stud
y to
A
DM
VA
IR
Pev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y of
a M
odif
ied
Vac
cini
a A
nkar
a (M
VA
) ex
pres
sing
HIV
-1 c
lade
C e
nv/g
ag-p
olan
d ne
f-ta
tfus
ion
gene
s (A
DM
VA
) va
ccin
e ad
min
iste
red
intr
amus
cula
rly
to H
IV u
ninf
ecte
d, h
ealt
hy v
olun
teer
s
2006
NC
T00
3760
90A
pha
se I
dou
ble-
blin
d, r
ando
mis
ed, d
ose-
esca
lati
ng, p
lace
bo-c
ontr
olle
d st
udy
of
MV
A-C
MD
RI
RP
safe
ty a
nd im
mun
ogen
icit
y of
WR
AIR
/NIH
live
rec
ombi
nant
MV
A-C
MD
R
(HIV
-1 C
M23
5 en
v/ C
M24
0 ga
g/po
l) a
dmin
iste
red
by I
M o
r in
trad
erm
al r
oute
in
HIV
uni
nfec
ted
adul
ts
2006
NC
T00
3866
33A
pha
se I
, ope
n, s
eque
ntia
l vac
cina
tion
stu
dy o
n sa
fety
and
tol
erab
ility
of
two
MV
A-m
BN
32I
NL
RP
diff
eren
t do
ses
of a
rec
ombi
nant
MV
A H
IV p
olyt
ope
vacc
ine
(MV
A-m
BN
32)
in
HIV
-neg
ativ
e 18
–50
year
old
hea
lthy
vol
unte
ers
2006
NC
T00
3900
78Si
ngle
-blin
d, r
ando
mis
ed, c
ontr
olle
d, p
hase
I/I
I va
ccin
atio
n st
udy
on s
afet
y an
d M
VA
-mB
N32
I/II
RT
imm
unog
enic
ity
of a
rec
ombi
nant
MV
A-H
IV p
olyt
ope
vacc
ine
(MV
A-m
BN
32)
in
MV
A-B
NH
IV-1
infe
cted
pat
ient
s w
ith
CD
4 co
unts
> 2
50/µ
l
Rec
omb
inan
t m
icro
bia
l va
ccin
es
Can
aryp
ox
1999
NC
T00
0009
04Sa
fety
and
eff
ecti
vene
ss o
f an
ti-H
IV v
acci
nes
in H
IV-n
egat
ive
adul
tsA
LV
AC
(2)1
20(B
,MN
)GN
PI
CP
(vC
P14
52)
gp16
0 M
N/L
AI-
2A
LV
AC
(1)1
20(B
,MN
)GN
P
(vC
P14
33)
AL
VA
C-H
IV M
N12
0TM
G
(vC
P20
5)
2000
N
CT
0000
1136
A s
tudy
of
the
effe
ctiv
enes
s of
an
HIV
vac
cine
(A
LV
AC
vC
P20
5) t
o bo
ost
imm
une
AL
VA
C-H
IV M
N12
0TM
GI
NL
RP
func
tion
s in
HIV
-neg
ativ
e vo
lunt
eers
who
hav
e al
read
y re
ceiv
ed a
n H
IV v
acci
ne(v
CP
205)
Dat
a w
ere
cons
ider
ed, u
p to
and
inc
ludi
ng 1
1 N
ovem
ber
2007
. Rec
ords
of A
IDS
vac
cine
cli
nica
l tri
als
retr
ieve
d fr
om h
ttp:
//ww
w.c
linic
altr
ials
.gov
. A s
earc
h w
as p
erfo
rmed
by
usin
g th
e op
erat
ors
‘AID
S O
R H
IV’ i
n th
e D
isea
se o
r C
ondi
tion
fiel
d an
d ‘v
acci
ne’ i
n th
e E
xper
imen
tal T
reat
men
tfi
eld,
and
it i
nclu
ded
all t
rial
s th
at w
ere
no lo
nger
rec
ruit
ing
pati
ents
. Thi
s se
arch
pro
duce
d 19
7 re
sult
s, d
etai
ling
cli
nica
l tri
als
invo
lvin
g 85
dif
fere
nt v
acci
ne p
rodu
cts
(str
ain
spec
ific
ity
of r
ecom
bina
nt p
rote
ins,
for
exam
ple,
was
take
n in
toac
coun
t, m
eani
ng s
trai
n M
N r
ecom
bina
nt g
p120
was
con
side
red
a se
para
te v
acci
ne fr
om s
trai
n S
F-2
rec
ombi
nant
gp1
20).
The
dat
e th
e tr
ial w
as r
egis
tere
d is
not
nec
essa
rily
the
date
the
tria
l com
men
ced;
whe
re b
oth
date
s ar
e kn
own,
thes
e ar
e gi
ven,
wit
h th
e ea
rlie
st b
eing
199
9 w
hen
the
data
base
was
ini
tiat
ed, t
houg
h tr
ials
may
hav
e be
gun
prio
r to
this
date
(com
p. =
[tri
al] c
ompl
eted
). F
or tr
ial s
tatu
s, C
= C
ompl
eted
, T =
Ter
min
ated
, S =
Sus
pend
ed, N
LR
= N
o L
onge
r R
ecru
itin
g, N
YR
= N
ot Y
et R
ecru
itin
g, R
= R
ecru
itin
g.T
he fi
nal c
olum
n in
dica
tes
whe
ther
the
vacc
ine
was
pri
mar
ily
prev
enti
ve (P
) or
ther
apeu
tic
(T).
Inte
rven
tion
s ar
e sh
own
in p
lain
text
, und
erli
ned,
or
bold
text
, to
indi
cate
whi
chva
ccin
es w
ere
prev
ious
ly te
sted
in
chim
panz
ees,
giv
en th
e ca
veat
that
the
freq
uent
poo
r qu
alit
y of
vac
cine
inf
orm
atio
n re
quir
es th
is to
be
an e
duca
ted
gues
s: P
lain
text
= n
o ev
i-de
nce
foun
d fo
r pr
ior
test
ing
in c
him
panz
ees;
Und
erli
ned
text
= s
imil
ar b
ut n
ot i
dent
ical
to v
acci
ne te
sted
in
chim
panz
ees
(e.g
. sam
e pl
asm
id c
onta
inin
g sa
me
HIV
gen
e am
ong
othe
r ge
nes;
dif
fere
nt a
djuv
ant;
etc.
); B
old
text
= i
dent
ical
vac
cine
test
ed i
n ch
impa
nzee
s.
400 J. BaileyTa
ble
1:
con
tin
ued
Dat
eP
reve
ntiv
e/re
g’d
Tri
al I
DO
ffic
ial t
itle
Inte
rven
tion
sP
hase
Sta
tus
ther
apeu
tic
2000
NC
T00
0062
91Sa
fety
and
eff
ecti
vene
ss o
f ad
ding
eit
her
an H
IV v
acci
ne, i
nter
leuk
in-2
, or
both
to
AL
VA
C(2
)120
(B,M
N)G
NP
IIC
Ta
pati
ent’
s an
ti-H
IV d
rug
com
bina
tion
(vC
P14
52)
2000
NC
T00
0074
23Sa
fety
and
eff
ecti
vene
ss o
f th
e va
ccin
e A
LV
AC
-HIV
vC
P20
5 in
HIV
-neg
ativ
e ad
ult
AL
VA
C-H
IV M
N12
0TM
GI
CP
volu
ntee
rs in
Uga
nda
(vC
P20
5)
2001
NC
T00
0110
11V
acci
ne (
AL
VA
C-H
IV v
CP
1452
) us
e an
d in
term
itte
nt w
ithd
raw
al o
f an
ti-H
IV
AL
VA
C(2
)120
(B,M
N)G
NP
I/II
CT
drug
s in
pat
ient
s w
ith
HIV
(vC
P14
52)
2001
NC
T00
0135
72H
IV c
andi
date
vac
cine
, AL
VA
C-H
IV-1
, adm
inis
trat
ion
in H
IV-n
egat
ive
adul
tsA
LV
AC
-HIV
MN
120T
MG
IN
LR
P(v
CP
205)
2001
NC
T00
0136
63Im
mun
e th
erap
ies
and
anti
-HIV
the
rapy
wit
hdra
wal
in c
ontr
ollin
g vi
ral l
oad
AL
VA
C(2
)120
(B,M
N)G
NP
IIC
T(v
CP
1452
)
2001
NC
T00
0266
24Sa
fety
/imm
unog
enic
ity
of im
mun
isat
ions
of
AL
VA
C-D
C-S
C v
sA
LV
AC
-SC
AL
VA
C(2
)120
(B,M
N)G
NP
IN
LR
T(v
CP
1452
)
2001
NC
T00
0272
61Sa
fety
and
imm
une
resp
onse
stu
dy o
f hi
gh-d
ose
cana
rypo
x A
LV
AC
-HIV
vac
cine
A
LV
AC
(2)1
20(B
,MN
)GN
P
IN
LR
Pin
hea
lthy
, HIV
uni
nfec
ted
adul
ts(v
CP
1452
)
2003
NC
T00
0567
97T
hera
peut
ic H
IV v
acci
ne a
nd in
terl
euki
n-2
to in
crea
se t
he im
mun
e sy
stem
’s
AL
VA
C H
IV v
acci
neII
CT
resp
onse
to
HIV
(vC
P14
52)
2004
NC
T00
0768
17Sa
fety
and
eff
ecti
vene
ss o
f ad
min
iste
ring
an
HIV
vac
cine
in t
he g
roin
ver
sus
the
AL
VA
C-H
IV (
vCP
205)
IN
LR
Par
m
2004
NC
T00
0981
63A
pha
se I
stu
dy t
o ev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y of
AL
VA
C-H
IV
AL
VA
C-H
IV v
CP
1521
IN
LR
PvC
P15
21 in
infa
nts
born
to
HIV
-1 in
fect
ed w
omen
in U
gand
a
2005
NC
T00
2193
62A
pha
se I
I, r
ando
mis
ed, p
lace
bo-c
ontr
olle
d st
udy
to e
valu
ate
the
imm
unog
enic
ity
vCP
1452
IIN
LR
Tan
d th
e sa
fety
of
2 sc
hedu
les
of a
n ho
mol
ogou
s pr
ime–
boos
t w
ith
the
AL
VA
C-H
IV
vCP
1452
in c
hron
ical
ly H
IV in
fect
ed p
atie
nts
Rec
omb
inan
t m
icro
bia
l va
ccin
es
Ven
ezue
lan
Equ
ine
Enc
epha
liti
s al
phav
irus
2003
NC
T00
0637
78Sa
fety
of
an H
IV v
acci
ne (
AV
X10
1) in
HIV
uni
nfec
ted
volu
ntee
rs in
the
USA
AV
X10
1I
CP
and
Sout
h A
fric
a
Role of chimpanzees in AIDS vaccine research 401
Tab
le 1
: co
nti
nu
ed
Dat
eP
reve
ntiv
e/re
g’d
Tri
al I
DO
ffic
ial t
itle
Inte
rven
tion
sP
hase
Sta
tus
ther
apeu
tic
2004
NC
T00
0978
38A
pha
se I
, dos
e es
cala
tion
, saf
ety,
and
imm
unog
enic
ity
tria
l of
an a
lpha
viru
s H
IV-1
sub
type
C g
ag
IN
LR
Pre
plic
on H
IV-1
sub
type
C g
ag v
acci
ne (
AV
X10
1) in
hea
lthy
HIV
-1 u
ninf
ecte
d va
ccin
e, A
VX
101
adul
t pa
rtic
ipan
ts
Rec
omb
inan
t m
icro
bia
l va
ccin
es
Salm
onel
la t
yphi
2003
NC
T00
0625
30D
evel
opm
ent
of a
n or
al p
rim
e–bo
ost
AID
S va
ccin
e to
elic
it b
road
ly n
eutr
alis
ing
SCB
aL/M
9 (o
ral r
ecom
bina
nt
IN
YR
Pan
tibo
dies
aga
inst
HIV
-1S
alm
onel
la ty
phi
HIV
-1
gp12
0 va
ccin
e)
Rec
omb
inan
t m
icro
bia
l va
ccin
es
Mul
tipl
e
2004
NC
T00
0836
03Sa
fety
of
and
imm
une
resp
onse
to
two
HIV
vac
cine
for
mul
atio
ns (
rMV
A-H
IV a
nd
rMV
A-H
IV (
rMV
A-H
IVI
NL
RP
rFP
V-H
IV)
alon
e or
in c
ombi
nati
on in
HIV
uni
nfec
ted
adul
tsen
v/ga
g+
rM
VA
-HIV
ta
t/re
v/ne
f-R
T)
FP
V-H
IV
(rF
PV
-HIV
env
/gag
+
rFP
V-H
IV t
at/r
ev/n
ef-R
T)
2005
NC
T00
1075
49A
pha
se I
, ope
n-la
bel s
tudy
to
eval
uate
the
saf
ety
and
tole
rabi
lity
of r
ecom
bina
nt
rMV
A-H
IV (
env/
gag
IS
TH
IV-1
vac
cine
s in
HIV
-1 in
fect
ed y
oung
adu
lts
wit
h co
ntro
l of
HIV
-1 r
eplic
atio
n [T
BC
-M35
8]+
tat
/rev
/nef
-an
d on
sta
ble
HA
AR
TR
T [
TB
C-M
335)
]) r
FP
V-H
IV
(env
/gag
[T
BC
-F35
7] +
tat
/re
v/ne
f-R
T [
TB
C-F
349]
)
2006
NC
T00
3011
84A
pha
se I
clin
ical
tri
al t
o ev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y of
pG
A2/
JS7
pGA
2/JS
7 D
NA
IR
PD
NA
vac
cine
and
rec
ombi
nant
Mod
ifie
d V
acci
nia
Ank
ara/
HIV
62 v
acci
ne in
M
odif
ied
Vac
cini
ahe
alth
y, H
IV-1
uni
nfec
ted
adul
t pa
rtic
ipan
tsA
nkar
a/H
IV62
Dat
a w
ere
cons
ider
ed, u
p to
and
inc
ludi
ng 1
1 N
ovem
ber
2007
. Rec
ords
of A
IDS
vac
cine
cli
nica
l tri
als
retr
ieve
d fr
om h
ttp:
//ww
w.c
linic
altr
ials
.gov
. A s
earc
h w
as p
erfo
rmed
by
usin
g th
e op
erat
ors
‘AID
S O
R H
IV’ i
n th
e D
isea
se o
r C
ondi
tion
fiel
d an
d ‘v
acci
ne’ i
n th
e E
xper
imen
tal T
reat
men
tfi
eld,
and
it i
nclu
ded
all t
rial
s th
at w
ere
no lo
nger
rec
ruit
ing
pati
ents
. Thi
s se
arch
pro
duce
d 19
7 re
sult
s, d
etai
ling
cli
nica
l tri
als
invo
lvin
g 85
dif
fere
nt v
acci
ne p
rodu
cts
(str
ain
spec
ific
ity
of r
ecom
bina
nt p
rote
ins,
for
exam
ple,
was
take
n in
toac
coun
t, m
eani
ng s
trai
n M
N r
ecom
bina
nt g
p120
was
con
side
red
a se
para
te v
acci
ne fr
om s
trai
n S
F-2
rec
ombi
nant
gp1
20).
The
dat
e th
e tr
ial w
as r
egis
tere
d is
not
nec
essa
rily
the
date
the
tria
l com
men
ced;
whe
re b
oth
date
s ar
e kn
own,
thes
e ar
e gi
ven,
wit
h th
e ea
rlie
st b
eing
199
9 w
hen
the
data
base
was
ini
tiat
ed, t
houg
h tr
ials
may
hav
e be
gun
prio
r to
this
date
(com
p. =
[tri
al] c
ompl
eted
). F
or tr
ial s
tatu
s, C
= C
ompl
eted
, T =
Ter
min
ated
, S =
Sus
pend
ed, N
LR
= N
o L
onge
r R
ecru
itin
g, N
YR
= N
ot Y
et R
ecru
itin
g, R
= R
ecru
itin
g.T
he fi
nal c
olum
n in
dica
tes
whe
ther
the
vacc
ine
was
pri
mar
ily
prev
enti
ve (P
) or
ther
apeu
tic
(T).
Inte
rven
tion
s ar
e sh
own
in p
lain
text
, und
erli
ned,
or
bold
text
, to
indi
cate
whi
chva
ccin
es w
ere
prev
ious
ly te
sted
in
chim
panz
ees,
giv
en th
e ca
veat
that
the
freq
uent
poo
r qu
alit
y of
vac
cine
inf
orm
atio
n re
quir
es th
is to
be
an e
duca
ted
gues
s: P
lain
text
= n
o ev
i-de
nce
foun
d fo
r pr
ior
test
ing
in c
him
panz
ees;
Und
erli
ned
text
= s
imil
ar b
ut n
ot i
dent
ical
to v
acci
ne te
sted
in
chim
panz
ees
(e.g
. sam
e pl
asm
id c
onta
inin
g sa
me
HIV
gen
e am
ong
othe
r ge
nes;
dif
fere
nt a
djuv
ant;
etc.
); B
old
text
= i
dent
ical
vac
cine
test
ed i
n ch
impa
nzee
s.
402 J. BaileyTa
ble
1:
con
tin
ued
Dat
eP
reve
ntiv
e/re
g’d
Tri
al I
DO
ffic
ial t
itle
Inte
rven
tion
sP
hase
Sta
tus
ther
apeu
tic
Au
tolo
gou
s ce
lls
2001
NC
T00
0192
66P
ilot
stud
y of
aut
olog
ous
T-c
ell t
rans
plan
tati
on w
ith
vacc
ine
driv
en e
xpan
sion
of
The
rape
utic
aut
olog
ous
IIC
Tan
ti-t
umou
r ef
fect
ors
afte
r cy
tore
duct
ive
ther
apy
in m
etas
tati
c pa
edia
tric
sar
com
asde
ndri
tic
cells
2003
NC
T00
0567
58H
IV v
acci
ne d
esig
ned
for
HIV
infe
cted
adu
lts
taki
ng a
nti-H
IV d
rugs
Aut
olog
ous
dend
riti
c ce
ll I
CT
HIV
vac
cina
tion
2003
NC
T00
0587
34T
hera
peut
ic v
acci
nati
on f
ollo
wed
by
trea
tmen
t in
terr
upti
on in
HIV
infe
cted
D
endr
itic
cel
ls p
ulse
d w
ith
IC
Tpa
tien
tsH
IV a
ntig
ens
[pep
tide
s]
2006
NC
T00
4021
42P
hase
II
stud
y of
aut
olog
ous
mye
loid
den
drit
ic c
ells
as
a ‘c
ellu
lar
adju
vant
’ for
a
Den
drit
ic c
ell v
acci
neI/
IIR
Tth
erap
euti
c H
IV-1
vac
cine
in e
arly
sta
ge H
IV-1
+pa
tien
ts (
DC
V-2
)
2006
NC
T00
4078
36P
hase
II
stud
y of
eff
icac
y, t
oler
abili
ty a
nd s
afet
y of
CD
4-sp
ecif
ic T
-cel
l vac
cine
in
T-c
ell v
acci
nati
onII
RT
HIV
infe
ctio
n
2007
NC
T00
5104
97P
hase
I/I
I ev
alua
tion
of
ther
apeu
tic
imm
unis
atio
n w
ith
auto
logo
us d
endr
itic
cel
ls
Aut
olog
ous
HIV
-1 A
pB D
C
I/II
RT
puls
ed w
ith
auto
logo
us, i
nact
ivat
ed H
IV-1
infe
cted
, apo
ptot
ic c
ells
vacc
ine
Mu
lti-
com
pon
ent
vacc
ines
D
NA
/pro
tein
2003
NC
T00
0612
43Sa
fety
of
and
imm
une
resp
onse
to
poly
vale
nt H
IV-1
vac
cine
in H
IV u
ninf
ecte
d H
IV-1
DN
A v
acci
ne w
ith
IN
LR
Pad
ults
prot
ein
vacc
ine
boos
t(m
ulti
ple
Env
ant
igen
s in
both
par
ts)
2003
NC
T00
0732
16Sa
fety
of
and
imm
une
resp
onse
to
a co
mbi
nati
on H
IV v
acci
ne r
egim
en in
HIV
C
lade
B g
agD
NA
/PL
G a
nd
IN
LR
Pun
infe
cted
adu
lts
env
DN
A/P
LG
mic
ropa
rtic
les
Cla
de B
rec
ombi
nant
, ol
igom
eric
gp1
40/M
F59
ad
juva
nt
Mu
lti-
com
pon
ent
vacc
ines
C
anar
ypox
/DN
A
1999
NC
T00
0010
90A
mul
tice
ntre
, ran
dom
ised
, pla
cebo
-con
trol
led,
dou
ble-
blin
ded,
pha
se I
tri
al t
o A
PL
400
-047
IC
Pev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y of
live
rec
ombi
nant
can
aryp
ox A
LV
AC
-A
LV
AC
-HIV
MN
120T
MG
HIV
vC
P20
5 co
mbi
ned
wit
h G
M-C
SF in
hea
lthy
, HIV
-1 u
ninf
ecte
d vo
lunt
eers
(vC
P20
5)A
ME
ND
ME
NT
4/3
0/99
: To
stud
y th
e sa
fety
of
follo
win
g 4
AL
VA
C im
mun
isat
ions
w
ith
a nu
clei
c ac
id g
ag/p
ol H
IV-1
imm
unog
en (
AP
L-4
00-0
47, W
yeth
-Led
erle
)
Role of chimpanzees in AIDS vaccine research 403
Tab
le 1
: co
nti
nu
ed
Dat
eP
reve
ntiv
e/re
g’d
Tri
al I
DO
ffic
ial t
itle
Inte
rven
tion
sP
hase
Sta
tus
ther
apeu
tic
Mu
lti-
com
pon
ent
vacc
ines
F
owlp
ox/D
NA
2003
NC
T00
0514
54E
valu
atio
n of
the
saf
ety
of a
nd im
mun
e re
spon
se t
o an
HIV
vac
cine
in h
ealt
hy
HIV
DN
A p
lasm
id v
acci
ne
I/II
CP
adul
tspl
us r
ecom
bina
nt f
owlp
ox
vect
or
2006
NC
T00
3334
24A
ran
dom
ised
, pla
cebo
-con
trol
led,
dou
ble-
blin
d, p
hase
I c
linic
al t
rial
to
eval
uate
P
rim
e: (
pHIS
-HIV
-AE
) I
NY
RP
the
safe
ty a
nd im
mun
ogen
icit
y of
a c
andi
date
pro
phyl
acti
c pH
IS-H
IV-A
E D
NA
en
codi
ng t
he H
IV-1
AE
pr
ime
and
rFP
V-H
IV-A
E b
oost
HIV
vac
cina
tion
str
ateg
yan
tige
ns, m
odif
ied
Gag
, Pol
, T
at/R
ev a
nd E
nvB
oost
: non
-rep
licat
ing,
re
com
bina
nt f
owlp
ox v
irus
(r
FP
V-H
IV-A
E)
enco
ding
the
H
IV-1
AE
ant
igen
s, m
odif
ied
Gag
, Pol
, Tat
/Rev
and
Env
2007
NC
T00
4767
49A
ran
dom
ised
, pla
cebo
-con
trol
led,
dou
ble-
blin
d, p
hase
I c
linic
al t
rial
to
eval
uate
pH
IS-H
IV-A
E D
NA
pri
me
IR
Pth
e sa
fety
and
imm
unog
enic
ity
of a
can
dida
te p
roph
ylac
tic
pHIS
-HIV
-AE
DN
A
rFP
V-H
IV-A
E b
oost
er
prim
e an
d rF
PV
-HIV
-AE
boo
st H
IV v
acci
nati
on s
trat
egy
vacc
ine
Mu
lti-
com
pon
ent
vacc
ines
A
deno
viru
s/D
NA
2005
NC
T00
1096
29V
RC
008
: A p
hase
I c
linic
al t
rial
of
a pr
ime–
boos
t H
IV-1
vac
cina
tion
sch
edul
e:
VR
C-H
IVD
NA
016-
00-V
PI
NL
RP
Mul
ticl
ade
DN
A v
acci
ne, V
RC
-HIV
DN
A01
6-00
-VP
, fol
low
ed b
y m
ulti
clad
e V
RC
-HIV
AD
V01
4-00
aden
ovir
al v
ecto
r va
ccin
e, V
RC
-HIV
AD
V01
4-00
-VP
, in
unin
fect
ed a
dult
vol
unte
ers
2005
NC
T00
1239
68A
pha
se I
/II
clin
ical
tri
al t
o ev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y of
a
VR
C-H
IVD
NA
016-
00-V
PI/
IIR
Pm
ulti
clad
e H
IV-1
DN
A p
lasm
id v
acci
ne, V
RC
-HIV
DN
A01
6-00
-VP
, boo
sted
by
a V
RC
-HIV
AD
V01
4-00
-VP
mul
ticl
ade
HIV
-1 r
ecom
bina
nt a
deno
viru
s-5
vect
or v
acci
ne, V
RC
-HIV
AD
V01
4-00
-VP
, in
HIV
uni
nfec
ted
adul
t vo
lunt
eers
in E
ast
Afr
ica
Dat
a w
ere
cons
ider
ed, u
p to
and
inc
ludi
ng 1
1 N
ovem
ber
2007
. Rec
ords
of A
IDS
vac
cine
cli
nica
l tri
als
retr
ieve
d fr
om h
ttp:
//ww
w.c
linic
altr
ials
.gov
. A s
earc
h w
as p
erfo
rmed
by
usin
g th
e op
erat
ors
‘AID
S O
R H
IV’ i
n th
e D
isea
se o
r C
ondi
tion
fiel
d an
d ‘v
acci
ne’ i
n th
e E
xper
imen
tal T
reat
men
tfi
eld,
and
it i
nclu
ded
all t
rial
s th
at w
ere
no lo
nger
rec
ruit
ing
pati
ents
. Thi
s se
arch
pro
duce
d 19
7 re
sult
s, d
etai
ling
cli
nica
l tri
als
invo
lvin
g 85
dif
fere
nt v
acci
ne p
rodu
cts
(str
ain
spec
ific
ity
of r
ecom
bina
nt p
rote
ins,
for
exam
ple,
was
take
n in
toac
coun
t, m
eani
ng s
trai
n M
N r
ecom
bina
nt g
p120
was
con
side
red
a se
para
te v
acci
ne fr
om s
trai
n S
F-2
rec
ombi
nant
gp1
20).
The
dat
e th
e tr
ial w
as r
egis
tere
d is
not
nec
essa
rily
the
date
the
tria
l com
men
ced;
whe
re b
oth
date
s ar
e kn
own,
thes
e ar
e gi
ven,
wit
h th
e ea
rlie
st b
eing
199
9 w
hen
the
data
base
was
ini
tiat
ed, t
houg
h tr
ials
may
hav
e be
gun
prio
r to
this
date
(com
p. =
[tri
al] c
ompl
eted
). F
or tr
ial s
tatu
s, C
= C
ompl
eted
, T =
Ter
min
ated
, S =
Sus
pend
ed, N
LR
= N
o L
onge
r R
ecru
itin
g, N
YR
= N
ot Y
et R
ecru
itin
g, R
= R
ecru
itin
g.T
he fi
nal c
olum
n in
dica
tes
whe
ther
the
vacc
ine
was
pri
mar
ily
prev
enti
ve (P
) or
ther
apeu
tic
(T).
Inte
rven
tion
s ar
e sh
own
in p
lain
text
, und
erli
ned,
or
bold
text
, to
indi
cate
whi
chva
ccin
es w
ere
prev
ious
ly te
sted
in
chim
panz
ees,
giv
en th
e ca
veat
that
the
freq
uent
poo
r qu
alit
y of
vac
cine
inf
orm
atio
n re
quir
es th
is to
be
an e
duca
ted
gues
s: P
lain
text
= n
o ev
i-de
nce
foun
d fo
r pr
ior
test
ing
in c
him
panz
ees;
Und
erli
ned
text
= s
imil
ar b
ut n
ot i
dent
ical
to v
acci
ne te
sted
in
chim
panz
ees
(e.g
. sam
e pl
asm
id c
onta
inin
g sa
me
HIV
gen
e am
ong
othe
r ge
nes;
dif
fere
nt a
djuv
ant;
etc.
); B
old
text
= i
dent
ical
vac
cine
test
ed i
n ch
impa
nzee
s.
404 J. BaileyTa
ble
1:
con
tin
ued
Dat
eP
reve
ntiv
e/re
g’d
Tri
al I
DO
ffic
ial t
itle
Inte
rven
tion
sP
hase
Sta
tus
ther
apeu
tic
2005
NC
T00
1240
07Sa
fety
of
and
imm
une
resp
onse
to
an a
deno
vira
l HIV
vac
cine
(V
RC
-HIV
AD
V01
4-V
RC
-HIV
AD
V01
4-00
-VP
IN
LR
P00
-VP
) w
ith
or w
itho
ut a
pla
smid
HIV
vac
cine
(V
RC
-HIV
DN
A01
6-00
-VP
) in
HIV
V
RC
-HIV
DN
A01
6-00
-VP
unin
fect
ed a
dult
s
2005
NC
T00
1259
70A
pha
se I
I cl
inic
al t
rial
to
eval
uate
the
saf
ety
and
imm
unog
enic
ity
of a
mul
ticl
ade
VR
C-H
IVD
NA
016-
00-V
PII
NL
RP
HIV
-1 D
NA
pla
smid
vac
cine
, VR
C-H
IVD
NA
016-
00-V
P, f
ollo
wed
by
a m
ulti
clad
e V
RC
-HIV
AD
V01
4-00
-VP
reco
mbi
nant
ade
novi
ral v
ecto
r H
IV-1
vac
cine
boo
st, V
RC
-HIV
AD
V01
4-00
-VP
, in
HIV
-1 u
ninf
ecte
d ad
ult
part
icip
ants
2005
NC
T00
2702
18A
pha
se I
clin
ical
tri
al t
o ev
alua
te im
mun
e re
spon
se k
inet
ics
and
safe
ty o
f tw
o V
RC
-HIV
AD
V01
4-00
-VP
IN
LR
Pdi
ffer
ent
prim
es, a
deno
vira
l vec
tor
vacc
ine
(VR
C-H
IVA
DV
014-
00-V
P)
and
DN
A
VR
C-H
IVD
NA
009-
00-V
Pva
ccin
e (V
RC
-HIV
DN
A00
9-00
-VP
), ea
ch f
ollo
wed
by
aden
ovir
al v
ecto
r bo
ost
in
heal
thy,
HIV
-1 u
ninf
ecte
d ad
ults
2005
NC
T00
2704
65V
RC
101:
A p
hase
I c
linic
al t
rial
to
eval
uate
the
saf
ety
and
imm
unog
enic
ity
of a
V
RC
-HIV
DN
A01
6-00
-VP
IN
LR
Tpr
ime–
boos
t H
IV-1
vac
cina
tion
sch
edul
e of
a 6
-pla
smid
mul
ticl
ade
HIV
-1 D
NA
V
RC
-HIV
AD
V01
4-00
-VP
vacc
ine,
VR
C-H
IVD
NA
016-
00-V
P, f
ollo
wed
by
a re
com
bina
nt m
ulti
clad
e ad
enov
iral
vec
tor
HIV
vac
cine
2006
NC
T00
3210
61V
RC
011
: A p
hase
I c
linic
al t
rial
of
intr
amus
cula
r, s
ubcu
tane
ous
and
intr
ader
mal
V
RC
-HIV
DN
A01
6-00
-VP
IN
LR
Pad
min
istr
atio
n of
an
HIV
-1 m
ulti
clad
e D
NA
vac
cine
, VR
C-H
IVD
NA
016-
00-V
P,
VR
C-H
IVA
DV
014-
00-V
Pan
d an
HIV
-1 m
ulti
clad
e ad
enov
iral
vec
tor
vacc
ine,
VR
C-H
IVA
DV
014-
00-V
P, i
n (‘
rAd5
vac
cine
’)un
infe
cted
adu
lt v
olun
teer
s
2006
NC
T00
3847
87A
pha
se I
B c
linic
al t
rial
to
com
pare
the
saf
ety,
tol
erab
ility
, and
imm
unog
enic
ity
of
VR
C-H
IVD
NA
009-
00-V
PI
RP
an H
IV-1
ade
novi
ral v
ecto
r bo
ost
adm
inis
tere
d in
tram
uscu
larl
y, in
trad
erm
ally
, V
RC
-HIV
AD
V01
4-00
-VP
or s
ubcu
tane
ousl
y af
ter
an H
IV-1
DN
A p
lasm
id v
acci
ne p
rim
e ad
min
iste
red
intr
amus
cula
rly
to h
ealt
hy a
deno
viru
s ty
pe 5
ser
opos
itiv
e H
IV-1
uni
nfec
ted
adul
ts
2006
NC
T00
4156
49A
pha
se I
I, r
ando
mis
ed, p
lace
bo-c
ontr
olle
d, d
oubl
e-bl
ind
tria
l to
eval
uate
the
V
RC
-HIV
DN
A01
6-00
-VP
IIN
YR
Psa
fety
and
imm
unog
enic
ity
of a
mul
ticl
ade
HIV
-1 D
NA
pla
smid
vac
cine
fol
low
ed
VR
C-H
IVA
DV
014-
00-V
Pby
rec
ombi
nant
, mul
ticl
ade
HIV
-1 a
deno
vira
l vec
tor
vacc
ine
in h
ealt
hy a
dult
vo
lunt
eers
at
risk
for
HIV
infe
ctio
n
2007
NC
T00
4727
19A
pha
se I
B c
linic
al t
rial
to
eval
uate
the
saf
ety
and
imm
unog
enic
ity
of
VR
C-H
IVA
DV
027-
00-V
PI
RP
reco
mbi
nant
ade
novi
ral s
erot
ype
35 (
rAd3
5) a
nd s
erot
ype
5 (r
Ad5
) H
IV-1
vac
cine
s V
RC
-HIV
AD
V03
8-00
-VP
whe
n gi
ven
in h
eter
olog
ous
prim
e–bo
ost
regi
men
s or
as
a bo
ost
to a
rec
ombi
nant
V
RC
-HIV
DN
A04
4-00
-VP
DN
A v
acci
ne in
hea
lthy
, HIV
-1 u
ninf
ecte
d ad
ult
part
icip
ants
wit
h pr
e-ex
isti
ng
imm
unit
y to
ade
novi
rus
sero
type
5 in
fect
ion
Role of chimpanzees in AIDS vaccine research 405
Tab
le 1
: co
nti
nu
ed
Dat
eP
reve
ntiv
e/re
g’d
Tri
al I
DO
ffic
ial t
itle
Inte
rven
tion
sP
hase
Sta
tus
ther
apeu
tic
2007
NC
T00
4980
56A
pha
se I
IB t
est-
of-c
once
pt, r
ando
mis
ed, d
oubl
e-bl
ind,
pla
cebo
-con
trol
led,
V
RC
-HIV
DN
A01
6-00
-VP
IIN
YR
Pin
tern
atio
nal c
linic
al t
rial
to
eval
uate
the
eff
icac
y, s
afet
y, a
nd im
mun
ogen
icit
y of
V
RC
-HIV
AD
V01
4-00
-VP
a m
ulti
clad
e H
IV-1
DN
A p
lasm
id v
acci
ne, V
RC
-HIV
DN
A01
6-00
-VP
, fol
low
ed b
y a
mul
ticl
ade
reco
mbi
nant
ade
novi
ral v
ecto
r va
ccin
e, V
RC
-HIV
AD
V01
4-00
-VP
, in
HIV
uni
nfec
ted
pers
ons
Mu
lti-
com
pon
ent
vacc
ines
V
acci
nia/
DN
A
2007
NC
T00
4283
37A
pha
se I
clin
ical
tri
al t
o ev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y of
DN
A v
acci
ne
EP
-123
3I
RP
EP
-123
3 an
d re
com
bina
nt M
VA
-HIV
pol
ytop
e va
ccin
e M
VA
-mB
N32
, sep
arat
ely
MV
A-m
BN
32an
d in
a c
ombi
ned
prim
e–bo
ost
regi
men
, whe
n gi
ven
to h
ealt
hy, v
acci
nia-
naïv
e,
HIV
-1 u
ninf
ecte
d ad
ults
2007
NC
T00
4900
74A
pha
se I
/II
tria
l to
com
pare
the
imm
unog
enic
ity
and
safe
ty o
f 3
DN
A-C
pri
me
DN
A-C
I/II
RP
follo
wed
by
1 N
YV
AC
-C b
oost
to
2 D
NA
-C p
rim
e fo
llow
ed b
y 2
NY
VA
C-C
boo
stN
YV
AC
-C
Mu
lti-
com
pon
ent
vacc
ines
V
acci
nia/
reco
mbi
nant
pro
tein
1999
NC
T00
0006
30P
hase
I s
afet
y an
d im
mun
ogen
icit
y tr
ial o
f va
ccin
ia-H
IV e
nvel
ope
reco
mbi
nant
H
IVA
C-1
eI
CP
vacc
ine
(HIV
AC
-1e)
in c
ombi
nati
on w
ith
solu
ble
reco
mbi
nant
env
elop
e va
ccin
e gp
160
vacc
ine
(Mic
roG
eneS
ys)
(gp1
60; V
axSy
n)
1999
NC
T00
0006
31A
pha
se I
ran
dom
ised
tri
al t
o ev
alua
te t
he s
afet
y an
d im
mun
ogen
icit
y of
H
IVA
C-1
eI
CP
vacc
inia
-HIV
env
elop
e re
com
bina
nt v
acci
ne (
HIV
AC
-1e)
in c
ombi
nati
on w
ith
gp16
0 va
ccin
e (M
icro
Gen
eSys
)so
lubl
e re
com
bina
nt e
nvel
ope
vacc
ine
(Vax
Syn)
1999
NC
T00
0006
83A
pha
se I
mul
tice
ntre
, ran
dom
ised
, dou
ble-
blin
d tr
ial t
o ev
alua
te t
he s
afet
y an
d H
IVA
C-1
eI
CP
imm
unog
enic
ity
of r
ecom
bina
nt v
acci
nia
viru
s ex
pres
sing
the
env
elop
e gp
160
vacc
ine
(Mic
roG
eneS
ys)
glyc
opro
tein
s of
hum
an im
mun
odef
icie
ncy
viru
s
Dat
a w
ere
cons
ider
ed, u
p to
and
inc
ludi
ng 1
1 N
ovem
ber
2007
. Rec
ords
of A
IDS
vac
cine
cli
nica
l tri
als
retr
ieve
d fr
om h
ttp:
//ww
w.c
linic
altr
ials
.gov
. A s
earc
h w
as p
erfo
rmed
by
usin
g th
e op
erat
ors
‘AID
S O
R H
IV’ i
n th
e D
isea
se o
r C
ondi
tion
fiel
d an
d ‘v
acci
ne’ i
n th
e E
xper
imen
tal T
reat
men
tfi
eld,
and
it i
nclu
ded
all t
rial
s th
at w
ere
no lo
nger
rec
ruit
ing
pati
ents
. Thi
s se
arch
pro
duce
d 19
7 re
sult
s, d
etai
ling
cli
nica
l tri
als
invo
lvin
g 85
dif
fere
nt v
acci
ne p
rodu
cts
(str
ain
spec
ific
ity
of r
ecom
bina
nt p
rote
ins,
for
exam
ple,
was
take
n in
toac
coun
t, m
eani
ng s
trai
n M
N r
ecom
bina
nt g
p120
was
con
side
red
a se
para
te v
acci
ne fr
om s
trai
n S
F-2
rec
ombi
nant
gp1
20).
The
dat
e th
e tr
ial w
as r
egis
tere
d is
not
nec
essa
rily
the
date
the
tria
l com
men
ced;
whe
re b
oth
date
s ar
e kn
own,
thes
e ar
e gi
ven,
wit
h th
e ea
rlie
st b
eing
199
9 w
hen
the
data
base
was
ini
tiat
ed, t
houg
h tr
ials
may
hav
e be
gun
prio
r to
this
date
(com
p. =
[tri
al] c
ompl
eted
). F
or tr
ial s
tatu
s, C
= C
ompl
eted
, T =
Ter
min
ated
, S =
Sus
pend
ed, N
LR
= N
o L
onge
r R
ecru
itin
g, N
YR
= N
ot Y
et R
ecru
itin
g, R
= R
ecru
itin
g.T
he fi
nal c
olum
n in
dica
tes
whe
ther
the
vacc
ine
was
pri
mar
ily
prev
enti
ve (P
) or
ther
apeu
tic
(T).
Inte
rven
tion
s ar
e sh
own
in p
lain
text
, und
erli
ned,
or
bold
text
, to
indi
cate
whi
chva
ccin
es w
ere
prev
ious
ly te
sted
in
chim
panz
ees,
giv
en th
e ca
veat
that
the
freq
uent
poo
r qu
alit
y of
vac
cine
inf
orm
atio
n re
quir
es th
is to
be
an e
duca
ted
gues
s: P
lain
text
= n
o ev
i-de
nce
foun
d fo
r pr
ior
test
ing
in c
him
panz
ees;
Und
erli
ned
text
= s
imil
ar b
ut n
ot i
dent
ical
to v
acci
ne te
sted
in
chim
panz
ees
(e.g
. sam
e pl
asm
id c
onta
inin
g sa
me
HIV
gen
e am
ong
othe
r ge
nes;
dif
fere
nt a
djuv
ant;
etc.
); B
old
text
= i
dent
ical
vac
cine
test
ed i
n ch
impa
nzee
s.
406 J. BaileyTa
ble
1:
con
tin
ued
Dat
eP
reve
ntiv
e/re
g’d
Tri
al I
DO
ffic
ial t
itle
Inte
rven
tion
sP
hase
Sta
tus
ther
apeu
tic
1999
NC
T00
0007
46A
pha
se I
, mul
tice
ntre
, ran
dom
ised
tri
al t
o ev
alua
te t
he s
afet
y an
d rg
p12
0/H
IV-1
SF
-2I
CP
imm
unog
enic
ity
of a
rec
ombi
nant
vac
cini
a-H
IV e
nvel
ope
vacc
ine
(HIV
AC
-1e)
in
Env
2-3
com
bina
tion
wit
h a
pane
l of
subu
nit
reco
mbi
nant
HIV
env
elop
e va
ccin
esH
IVA
C-1
e
1999
NC
T00
0008
66A
mul
tice
ntre
, ran
dom
ised
, pla
cebo
-con
trol
led,
dou
ble-
blin
d tr
ial t
o ev
alua
te t
he
MN
rgp
120/
HIV
-1—
CP
safe
ty a
nd im
mun
ogen
icit
y of
the
The
rion
rec
ombi
nant
vac
cini
a-H
IV-1
III
B
TB
C-3
B v
acci
neE
NV
/GA
G/P
OL
vac
cine
(T
CB
-3B
) an
d M
N r
gp12
0/H
IV-1
in a
lum
1999
NC
T00
0010
26A
pha
se I
, mul
tice
ntre
, ran
dom
ised
tri
al t
o ev
alua
te t
he s
afet
y an
d gp
160
vacc
ine
IC
Pim
mun
ogen
icit
y of
a r
ecom
bina
nt v
acci
nia-
HIV
env
elop
e va
ccin
e (H
IVA
C-1
e) in
(I
mm
un
o-A
G)
com
bina
tion
wit
h a
pane
l of
subu
nit
reco
mbi
nant
HIV
env
elop
e va
ccin
es in
rg
p12
0/H
IV-1
IIIB
vacc
inia
-naï
ve in
divi
dual
srg
p12
0/H
IV-1
MN
rgp
120/
HIV
-1 S
F-2
HIV
AC
-1e
1999
NC
T00
0022
61A
com
para
tive
pha
se I
clin
ical
stu
dy o
f H
IVA
C-1
e an
d sm
allp
ox (
vacc
inia
) H
IVA
C-1
eI
CP
vacc
ines
in p
revi
ousl
y (v
acci
nia)
vac
cina
ted
and
unva
ccin
ated
vol
unte
ers
gp16
0 va
ccin
e (M
icro
Gen
eSys
)
Mu
lti-
com
pon
ent
vacc
ines
F
owlp
ox/r
ecom
bina
nt p
rote
in
2006
NC
T00
3329
30A
n ex
tens
ion
stud
y to
pro
toco
l VIR
-NC
HR
-01
to a
sses
s th
e an
tire
trov
irol
ogic
al
Rec
ombi
nant
fow
lpox
viru
s I/
IIC
T
prop
erti
es o
f a
ther
apeu
tic
HIV
vac
cine
can
dida
te b
ased
on
reco
mbi
nant
fow
lpox
(r
FP
V)
expr
essi
ng H
IV
viru
s (r
FP
V)
(IT
V e
xten
sion
stu
dy)
gag-
pol a
ntig
ens
HIV
gag
-pol
ant
igen
s an
d in
terf
eron
-gam
ma
(IF
N-γ
)
Mu
lti-
com
pon
ent
vacc
ines
C
anar
ypox
/rec
ombi
nant
pro
tein
1999
NC
T00
0008
13A
pha
se I
saf
ety
and
imm
unog
enic
ity
tria
l of
live
reco
mbi
nant
can
aryp
ox-g
p160
A
LV
AC
-HIV
gp1
60M
N
IC
PM
N (
AL
VA
C v
CP
125,
HIV
-1 g
p160
MN
) in
HIV
-1 u
ninf
ecte
d ad
ult
volu
ntee
rs(v
CP
125)
rgp
120/
HIV
-1 S
F-2
1999
NC
T00
0008
47A
pha
se I
saf
ety
and
imm
unog
enic
ity
tria
l of
live
reco
mbi
nant
can
aryp
ox A
LV
AC
-A
LV
AC
-HIV
MN
120T
MG
IC
PH
IV (
vCP
205)
and
HIV
-1 S
F-2
rgp
120
in H
IV-1
uni
nfec
ted
adul
t vo
lunt
eers
(vC
P20
5)rg
p12
0/H
IV-1
SF
-2
1999
NC
T00
0008
71A
pha
se I
I sa
fety
and
imm
unog
enic
ity
tria
l of
live
reco
mbi
nant
can
aryp
ox
MN
rgp
120/
HIV
-1 a
nd
II
NL
RP
AL
VA
C-H
IV v
CP
205
wit
h or
wit
hout
HIV
-1 S
F-2
rgp
120
in H
IV-1
uni
nfec
ted
GN
E8
rgp
120/
HIV
-1ad
ult
volu
ntee
rsM
N r
gp12
0/H
IV-1
an
d
A24
4 rg
p12
0/H
IV-1
AL
VA
C-H
IV M
N12
0TM
G(v
CP
205)
rgp
120/
HIV
-1 S
F-2
Role of chimpanzees in AIDS vaccine research 407
Tab
le 1
: co
nti
nu
ed
Dat
eP
reve
ntiv
e/re
g’d
Tri
al I
DO
ffic
ial t
itle
Inte
rven
tion
sP
hase
Sta
tus
ther
apeu
tic
1999
NC
T00
0008
79A
stu
dy o
f th
e ef
fect
s of
giv
ing
two
anti
-HIV
vac
cine
s to
bab
ies
of H
IV-p
osit
ive
AL
VA
C(2
)120
(B,M
N)G
NP
IN
LR
P/T
mot
hers
(vC
P14
52)
MN
rgp
120/
HIV
-1 a
nd
G
NE
8 rg
p12
0/H
IV-1
AL
VA
C-H
IV M
N12
0TM
G(v
CP
205)
1999
NC
T00
0008
84A
ran
dom
ised
pha
se I
saf
ety
and
imm
unog
enic
ity
tria
l of
live
reco
mbi
nant
M
N r
gp12
0/H
IV-1
an
d
IN
LR
Pca
nary
pox
AL
VA
C-H
IV v
CP
205
deliv
ered
by
alte
rnat
e m
ucos
al r
oute
s in
HIV
-1
GN
E8
rgp
120/
HIV
-1un
infe
cted
adu
lt v
olun
teer
sA
LV
AC
-HIV
MN
120T
MG
(vC
P20
5)
1999
NC
T00
0009
46A
stu
dy t
o te
st t
he s
afet
y of
thr
ee e
xper
imen
tal H
IV v
acci
nes
HIV
p24
/MF
59 v
acci
neI
NL
RP
AL
VA
C-H
IV M
N12
0TM
G(v
CP
205)
rgp
120/
HIV
-1 S
F-2
1999
NC
T00
0010
55A
pha
se I
saf
ety
and
imm
unog
enic
ity
tria
l of
live
reco
mbi
nant
can
aryp
ox
AL
VA
C-H
IV M
N12
0TM
GI
CP
AL
VA
C-H
IV (
vCP
205)
in H
IV-1
uni
nfec
ted
adul
t vo
lunt
eers
(vC
P20
5)rg
p12
0/H
IV-1
SF
-2
1999
NC
T00
0010
72A
pha
se I
saf
ety
and
imm
unog
enic
ity
tria
l of
live
reco
mbi
nant
can
aryp
ox A
LV
AC
-A
LV
AC
-HIV
MN
120T
MG
NP
I
CP
HIV
vC
P30
0 an
d H
IV-1
SF
-2 r
gp12
0 in
HIV
-1 u
ninf
ecte
d ad
ult
volu
ntee
rs(v
CP
300)
rgp
120/
HIV
-1 S
F-2
1999
NC
T00
0010
76A
pha
se I
saf
ety
and
imm
unog
enic
ity
tria
l of
live
reco
mbi
nant
can
aryp
ox
AL
VA
C-H
IV M
N12
0TM
GI
CP
AL
VA
C-H
IV (
vCP
205)
and
HIV
-1 S
F-2
rgp
120
in H
IV-1
uni
nfec
ted
volu
ntee
rs t
o (v
CP
205)
eval
uate
acc
eler
ated
vac
cine
sch
edul
esA
LV
AC
-RG
rab
ies
glyc
opro
tein
(vC
P65
)rg
p12
0/H
IV-1
SF
-2
Dat
a w
ere
cons
ider
ed, u
p to
and
inc
ludi
ng 1
1 N
ovem
ber
2007
. Rec
ords
of A
IDS
vac
cine
cli
nica
l tri
als
retr
ieve
d fr
om h
ttp:
//ww
w.c
linic
altr
ials
.gov
. A s
earc
h w
as p
erfo
rmed
by
usin
g th
e op
erat
ors
‘AID
S O
R H
IV’ i
n th
e D
isea
se o
r C
ondi
tion
fiel
d an
d ‘v
acci
ne’ i
n th
e E
xper
imen
tal T
reat
men
tfi
eld,
and
it i
nclu
ded
all t
rial
s th
at w
ere
no lo
nger
rec
ruit
ing
pati
ents
. Thi
s se
arch
pro
duce
d 19
7 re
sult
s, d
etai
ling
cli
nica
l tri
als
invo
lvin
g 85
dif
fere
nt v
acci
ne p
rodu
cts
(str
ain
spec
ific
ity
of r
ecom
bina
nt p
rote
ins,
for
exam
ple,
was
take
n in
toac
coun
t, m
eani
ng s
trai
n M
N r
ecom
bina
nt g
p120
was
con
side
red
a se
para
te v
acci
ne fr
om s
trai
n S
F-2
rec
ombi
nant
gp1
20).
The
dat
e th
e tr
ial w
as r
egis
tere
d is
not
nec
essa
rily
the
date
the
tria
l com
men
ced;
whe
re b
oth
date
s ar
e kn
own,
thes
e ar
e gi
ven,
wit
h th
e ea
rlie
st b
eing
199
9 w
hen
the
data
base
was
ini
tiat
ed, t
houg
h tr
ials
may
hav
e be
gun
prio
r to
this
date
(com
p. =
[tri
al] c
ompl
eted
). F
or tr
ial s
tatu
s, C
= C
ompl
eted
, T =
Ter
min
ated
, S =
Sus
pend
ed, N
LR
= N
o L
onge
r R
ecru
itin
g, N
YR
= N
ot Y
et R
ecru
itin
g, R
= R
ecru
itin
g.T
he fi
nal c
olum
n in
dica
tes
whe
ther
the
vacc
ine
was
pri
mar
ily
prev
enti
ve (P
) or
ther
apeu
tic
(T).
Inte
rven
tion
s ar
e sh
own
in p
lain
text
, und
erli
ned,
or
bold
text
, to
indi
cate
whi
chva
ccin
es w
ere
prev
ious
ly te
sted
in
chim
panz
ees,
giv
en th
e ca
veat
that
the
freq
uent
poo
r qu
alit
y of
vac
cine
inf
orm
atio
n re
quir
es th
is to
be
an e
duca
ted
gues
s: P
lain
text
= n
o ev
i-de
nce
foun
d fo
r pr
ior
test
ing
in c
him
panz
ees;
Und
erli
ned
text
= s
imil
ar b
ut n
ot i
dent
ical
to v
acci
ne te
sted
in
chim
panz
ees
(e.g
. sam
e pl
asm
id c
onta
inin
g sa
me
HIV
gen
e am
ong
othe
r ge
nes;
dif
fere
nt a
djuv
ant;
etc.
); B
old
text
= i
dent
ical
vac
cine
test
ed i
n ch
impa
nzee
s.
408 J. BaileyTa
ble
1:
con
tin
ued
Dat
eP
reve
ntiv
e/re
g’d
Tri
al I
DO
ffic
ial t
itle
Inte
rven
tion
sP
hase
Sta
tus
ther
apeu
tic
1999
NC
T00
0045
79A
pha
se I
, dos
e-ra
ngin
g tr
ial o
f th
e P
aste
ur M
erie
ux C
onna
ught
(P
MC
) ol
igom
eric
gp
160
MN
/LA
I-2
IC
PH
IV-1
gp1
60M
N/L
AI-
2 va
ccin
e al
one
or p
rim
ed w
ith
live
reco
mbi
nant
A
LV
AC
-HIV
MN
120T
MG
AL
VA
C-H
IV (
vCP
205)
in H
IV s
eron
egat
ive
adul
ts(v
CP
205)
2000
NC
T00
0065
09A
stu
dy o
f th
e sa
fety
and
eff
ecti
vene
ss o
f an
HIV
vac
cine
for
HIV
-pos
itiv
e A
LV
AC
(2)1
20(B
,MN
)GN
PI
NL
RT
pati
ents
rec
eivi
ng a
nti-H
IV d
rugs
for
at
leas
t 2
year
s(v
CP
1452
)gp
160
MN
/LA
I-2
2000
NC
T00
0073
32Sa
fety
and
imm
une
resp
onse
stu
dy o
f th
e va
ccin
e A
LV
AC
vC
P14
52 a
lone
or
in
AL
VA
C(2
)120
(B,M
N)G
NP
IIC
Pco
mbi
nati
on w
ith
AID
SVA
X B
/B(v
CP
1452
)M
N r
gp12
0/H
IV-1
an
d
GN
E8
rgp
120/
HIV
-1
2001
NC
T00
0110
37A
LV
AC
-HIV
vC
P14
52 a
lone
and
com
bine
d w
ith
MN
rgp
120
AL
VA
C(2
)120
(B,M
N)G
NP
IIN
LR
P(v
CP
1452
)M
N r
gp12
0/H
IV-1
2005
NC
T00
2230
80A
pha
se I
II t
rial
of
Ave
ntis
Pas
teur
live
rec
ombi
nant
AL
VA
C-H
IV (
vCP
1521
) A
LV
AC
-HIV
vC
P15
21II
IN
LR
P(c
omp
.pr
imin
g w
ith
Vax
Gen
gp1
20 B
/E (
AID
SVA
X B
/E)
boos
ting
in H
IV u
ninf
ecte
d A
IDS
VA
X g
p12
0 B
/E20
03)
Tha
i adu
lts
2006
NC
T00
3371
81E
xten
ded
eval
uati
on o
f th
e vi
rolo
gic,
imm
unol
ogic
, and
clin
ical
cou
rse
of
AL
VA
C-H
IV (
vCP
1521
)—
RP
volu
ntee
rs w
ho b
ecom
e H
IV-1
infe
cted
dur
ing
part
icip
atio
n in
a p
hase
III
vac
cine
A
IDS
VA
X B
/E: b
ival
ent
tria
l of
AL
VA
C-H
IV a
nd A
IDSV
AX
B/E
HIV
gp
120
Mu
lti-
com
pon
ent
vacc
ines
Sa
lmon
ella
typ
hi/r
ecom
bina
nt p
rote
in
1999
NC
T00
0008
68A
stu
dy t
o ev
alua
te t
he s
afet
y an
d ef
fect
iven
ess
of H
IV-1
LA
I gp
120
(an
HIV
S
alm
onel
la ty
phi
CV
D
IC
Pva
ccin
e) g
iven
wit
h or
wit
hout
HIV
-1 M
N r
gp12
0 (a
noth
er H
IV v
acci
ne)
to
908-
HIV
-1 L
AI
gp12
0 H
IV-n
egat
ive
volu
ntee
rs(V
VG
203
)rg
p12
0/H
IV-1
MN
Mu
lti-
com
pon
ent
vacc
ines
C
anar
ypox
/inac
tiva
ted
viru
s
2000
NC
T00
0057
58E
ffec
tive
ness
of
givi
ng a
n H
IV v
acci
ne (
Rem
une)
to
HIV
-pos
itiv
e pa
tien
ts
AL
VA
C(2
)120
(B,M
N)G
NP
III
CT
rece
ivin
g an
ant
i-HIV
dru
g co
mbi
nati
on(v
CP
1452
)H
IV-1
imm
unog
en
2000
NC
T00
0064
95Im
mun
e re
spon
ses
in H
IV-p
osit
ive
pati
ents
rec
eivi
ng a
n an
ti-H
IV d
rug
AL
VA
C(2
)120
(B,M
N)G
NP
IC
Tco
mbi
nati
on w
hen
give
n th
e H
IV v
acci
nes
Rem
une
and
vCP
1452
(vC
P14
52)
HIV
-1 im
mun
ogen
(R
emun
e)
Role of chimpanzees in AIDS vaccine research 409
Tab
le 1
: co
nti
nu
ed
Dat
eP
reve
ntiv
e/re
g’d
Tri
al I
DO
ffic
ial t
itle
Inte
rven
tion
sP
hase
Sta
tus
ther
apeu
tic
2005
NC
T00
2128
88A
pilo
t st
udy
to d
eter
min
e th
e im
pact
of
ther
apeu
tic
HIV
vac
cina
tion
fol
low
ed b
y R
emun
eI/
IIR
Ta
sche
dule
d in
terr
upti
on o
f an
tire
trov
iral
the
rapy
on
HIV
-spe
cifi
c im
mun
e A
LV
AC
func
tion
and
vir
olog
ic r
ebou
nd in
pat
ient
s w
ith
prol
onge
d vi
ral s
uppr
essi
on
Mu
lti-
com
pon
ent
vacc
ines
C
anar
ypox
/pep
tide
or
lipo
pept
ide
2004
NC
T00
0760
63A
stu
dy o
f L
IPO
-5 a
nd A
LV
AC
-HIV
(vC
P14
52)
as p
ossi
ble
HIV
vac
cine
sA
LV
AC
-HIV
(vC
P14
52)
I/II
NL
RP
LIP
O-5
2005
NC
T00
1966
51R
ando
mis
ed s
tudy
on
HIV
imm
une
and
viro
logi
cal r
espo
nses
fol
low
ing
the
LIP
O-6
TII
TT
adm
inis
trat
ion
of I
L-2
eit
her
alon
e or
com
bine
d to
AL
VA
C-H
IV 1
433
and
HIV
A
LV
AC
HIV
143
3lip
opep
tide
s (L
IPO
-6T
) in
pat
ient
s tr
eate
d ea
rly
wit
h H
AA
RT
dur
ing
prim
ary
IL-2
infe
ctio
n. A
NR
S 09
5 P
RIM
OV
AC
Mu
lti-
com
pon
ent
vacc
ines
V
irus
-lik
e pa
rtic
les/
pept
ide
1999
NC
T00
0024
28A
pha
se I
/II
safe
ty a
nd im
mun
ogen
icit
y tr
ial o
f U
BI
mic
ropa
rtic
ulat
e m
onov
alen
t H
IV-1
pep
tide
vac
cine
,I/
IIC
P(H
IV-1
MN
) br
anch
ed p
epti
de v
acci
ne in
HIV
-1 s
eron
egat
ive
hum
an s
ubje
cts
mic
ropa
rtic
ulat
e m
onov
alen
trg
p120
/HIV
-1M
N m
onov
alen
toc
tam
eric
V3
pept
ide
vacc
ine
Un
kn
own
2007
NC
T00
4345
12A
dos
e-ra
ngin
g st
udy
to c
ompa
re t
he s
afet
y an
d im
mun
ogen
icit
y of
a c
andi
date
H
IV v
acci
ne 7
3246
1I/
IIN
LR
PH
IV v
acci
ne 7
3246
1, a
djuv
ante
d or
not
, adm
inis
tere
d ac
cord
ing
to a
0, 1
, 6
mon
ths
sche
dule
to
heal
thy
adul
t H
IV s
eron
egat
ive
volu
ntee
rs
Dat
a w
ere
cons
ider
ed, u
p to
and
inc
ludi
ng 1
1 N
ovem
ber
2007
. Rec
ords
of A
IDS
vac
cine
cli
nica
l tri
als
retr
ieve
d fr
om h
ttp:
//ww
w.c
linic
altr
ials
.gov
. A s
earc
h w
as p
erfo
rmed
by
usin
g th
e op
erat
ors
‘AID
S O
R H
IV’ i
n th
e D
isea
se o
r C
ondi
tion
fiel
d an
d ‘v
acci
ne’ i
n th
e E
xper
imen
tal T
reat
men
tfi
eld,
and
it i
nclu
ded
all t
rial
s th
at w
ere
no lo
nger
rec
ruit
ing
pati
ents
. Thi
s se
arch
pro
duce
d 19
7 re
sult
s, d
etai
ling
cli
nica
l tri
als
invo
lvin
g 85
dif
fere
nt v
acci
ne p
rodu
cts
(str
ain
spec
ific
ity
of r
ecom
bina
nt p
rote
ins,
for
exam
ple,
was
take
n in
toac
coun
t, m
eani
ng s
trai
n M
N r
ecom
bina
nt g
p120
was
con
side
red
a se
para
te v
acci
ne fr
om s
trai
n S
F-2
rec
ombi
nant
gp1
20).
The
dat
e th
e tr
ial w
as r
egis
tere
d is
not
nec
essa
rily
the
date
the
tria
l com
men
ced;
whe
re b
oth
date
s ar
e kn
own,
thes
e ar
e gi
ven,
wit
h th
e ea
rlie
st b
eing
199
9 w
hen
the
data
base
was
ini
tiat
ed, t
houg
h tr
ials
may
hav
e be
gun
prio
r to
this
date
(com
p. =
[tri
al] c
ompl
eted
). F
or tr
ial s
tatu
s, C
= C
ompl
eted
, T =
Ter
min
ated
, S =
Sus
pend
ed, N
LR
= N
o L
onge
r R
ecru
itin
g, N
YR
= N
ot Y
et R
ecru
itin
g, R
= R
ecru
itin
g.T
he fi
nal c
olum
n in
dica
tes
whe
ther
the
vacc
ine
was
pri
mar
ily
prev
enti
ve (P
) or
ther
apeu
tic
(T).
Inte
rven
tion
s ar
e sh
own
in p
lain
text
, und
erli
ned,
or
bold
text
, to
indi
cate
whi
chva
ccin
es w
ere
prev
ious
ly te
sted
in
chim
panz
ees,
giv
en th
e ca
veat
that
the
freq
uent
poo
r qu
alit
y of
vac
cine
inf
orm
atio
n re
quir
es th
is to
be
an e
duca
ted
gues
s: P
lain
text
= n
o ev
i-de
nce
foun
d fo
r pr
ior
test
ing
in c
him
panz
ees;
Und
erli
ned
text
= s
imil
ar b
ut n
ot i
dent
ical
to v
acci
ne te
sted
in
chim
panz
ees
(e.g
. sam
e pl
asm
id c
onta
inin
g sa
me
HIV
gen
e am
ong
othe
r ge
nes;
dif
fere
nt a
djuv
ant;
etc.
); B
old
text
= i
dent
ical
vac
cine
test
ed i
n ch
impa
nzee
s.
human trials (43). The ability of recombinant gp160protein to confer protection was also shown inchimpanzees (44, 45), as it was in other studieswhere a variety of vaccines were also protective tochimpanzees, such as whole inactivated virus,recombinant vaccinia-gp160, the recombinant pro-teins p18 gag, p27 nef and p23 vif, and peptideimmunogens (46, 47). This protection in chim-panzees extended to challenge with HIV-infectedlymphocytes, as well as with free virus (48).Recombinant gp160 protein was also protective inchimpanzees when boosted with V3 peptides (49,50).
Also, one of the two aforementioned AIDSVAXvaccines, produced by VaxGen, was the first candi-date HIV vaccine to complete a Phase III trial (43),closely followed by the other. AIDSVAX B/B (com-prising gp120 envelope proteins from two clade Bstrains of HIV, MN and GNE8) failed to protectmore than 5000 trial participants (mainly gay men)at high risk of HIV infection (51), and AIDSVAX B/E(comprising gp120 from strains MN and A244 [cladeE]) failed to provide protection against HIV infectionfor over 2500 users of injected drugs in Thailand(52), despite repeated booster immunisationsthroughout the study. These failures occurreddespite the fact that AIDSVAX achieved the greatestimmune response of any vaccine of this type (35).
The dearth of active clinical trials of this kind ofvaccine, coupled with high-profile failures, hasprompted some to consider that the concept of theinduction of neutralising antibodies as an HIV vac-cine strategy has ‘run aground’ (53). Evidence sug-gests this was recognised by many scientists sometime ago, there having been a distinct re-focusing ofefforts to develop an effective vaccine toward otherapproaches, as well as an admission that recombi-nant proteins could be used only as part of a‘prime–boost’ vaccine regimen.
Peptide/lipopeptide vaccines
Peptide/lipopeptide vaccines constitute 14 (7%) ofthe 197 registered clinical trials, and involve ninedifferent vaccines. They contain small fragments ofHIV proteins, rather than the complete molecules,which makes them simpler and cheaper. Thesefragments often contain the most immunogenicparts of the HIV proteins, targeting an immuneresponse to dominant T-cell epitopes and neutralis-ing determinants (54), and several peptides fromdifferent strains of HIV can be contained in one vac-cine. More recently, they have been combined withlipid molecules to form ‘lipopeptides’, in order toincrease their immunogenicity (55).
In common with recombinant protein vaccines,most trials of peptides/lipopeptides were registered,and therefore took place, in and around 1999. Justfour trials have been registered since 2004. All but
one (13/14) of the trials are Phase I trials; theexception is a Phase II trial of the LIPO-5 vaccine,which is listed as no longer recruiting participants.As may be expected due to the lack of trial progres-sion, and in common with trials of recombinant pro-tein vaccines, success has not been reported (2, 35,56, 57), despite, for example, reports of potent andlong-lasting B-cell and T-cell responses to lipopep-tide immunisation in chimpanzees (58).
No chimpanzee trials of this type of vaccine werelisted in the NHPVT database.
Virus-like particles
Virus-like particles (VLPs, also known as ‘pseudoviri-ons’) can be generated by the in vitro or in vivo (suchas in transfected cells) production of HIV-1 viral pro-teins, which can spontaneously assemble into parti-cles. Only two registered trials were found inClinicalTrials.gov, which were both Phase I trialsregistered in 1999. One of these (‘HIV-1 Pseudo -virion’ vaccine) was terminated prior to completion.
Young et al. (31), however, report that the othervaccine (HIV p17/p24:Ty-VLP) has also been testedin a Phase II trial (59). In contrast to resultsobtained in mice, vaccinated individuals had lowlevels of both humoral and cell-mediated immunity.This vaccine also showed no significant effect ondisease progression in HIV-infected volunteers in along-term follow-up study (60). Young et al. (31)also cite another Phase I trial with VLPp24 vaccine,which failed to augment immunity to HIV ininfected patients (61).
No chimpanzee trials of this type of vaccine werelisted in the NHPVT database.
DNA vaccines
Twenty-five (13%) of the 197 registered trialsinvolved 14 different DNA vaccines, whereby plas-mids containing HIV genes are used to induceimmunity to the virus when injected intramuscu-larly. Cells exposed to such plasmids ‘ingest’ theDNA, which is then transcribed and translated bythe host cells to produce the cognate viral proteins.When ‘proof of concept’ was initially demonstratedby injecting DNA into the muscles of mice (62), itwas subsequently shown that proteins produced inthis manner could induce significant humoral andcellular immune responses (63–65).
The NHPVT database contained three records ofDNA vaccine trials in chimpanzees (NHP .226,NHP .202 and NHP .71), all of which demonstratedimmunogenicity. One trial provided protectionfrom HIV infection to an uninfected chimpanzee,and one vaccine induced an indefinite decrease inviral load, when used as a therapeutic vaccine forinfected chimpanzees. The other trial was also ther-
410 J. Bailey
apeutic in nature, and also decreased viral load,though this effect was transient.
Twenty-five (13%) of the 197 registered trialsexamined 14 DNA vaccines. All but three of these25 trials were Phase I trials, with the remainingthree being Phase I/II trials. Just eight of the 25 tri-als had been completed at the time of writing, andone trial of a gag DNA vaccine registered in 2005has already been terminated.
Many researchers thought that DNA vaccinationwould revolutionise vaccine development for manydiseases, not just for HIV. The first human trialinvolved HIV-1 strain MN env gp160 and rev genes(66), and although marginal increases in anti-gp160cytotoxic T-lymphocyte (CTL) activity were observedin a small number of volunteers, there was nochange in CD4+ T-cell count or plasma viral load.Subsequent trials have continued to fall short: forexample, plasmids encoding nef, tat or env geneshave been only slightly immunogenic (67, 68), andjust three of the trials are anything other than PhaseI trials (i.e. Phase I/II). This disappointment isreflected in the opinions of authors of several recentreviews on the topic: “Although immunisation withDNA plasmids that contain HIV inserts has elicitedsubstantial cellular responses in mice and nonhu-man primates, these products have been poorlyimmunogenic in humans.” (5); “Plasmid DNA con-structs have proved to be effective immunogens inmice for eliciting cellular immune responses and forpriming antibody responses. It is now clear, however,that DNA vaccines are less immunogenic in non-human primates than they are in mice, and even lessimmunogenic in humans than in non-human pri-mates.” (69); and “Although DNA vaccines areimmunogenic in mice and monkeys (includingneonates), current vaccines are poorly immunogenicwhen administered alone to people.” (70).
There is ample supporting evidence for such opin-ions. DNA vaccination has been shown in numerousstudies to produce strong virus-specific immuneresponses, and to be protective against HIV infec-tion in chimpanzees (71–74).
The initial failures with ‘native’ DNA vaccineshave led to efforts to augment vaccine DNA expres-sion by using co-expressed cytokines (notably inter-leukin [IL]-12 and IL-15; 5) and adjuvants (55, 75,76; see Table 1), by improving DNA delivery tech-niques (77, 78), by using the DNA vaccines in acombination ‘prime–boost’ approach, and by usinga variety of genetic techniques, such as promotermodification and codon optimisation (79, 80).
Recombinant microbial vaccines (RMVs)
RMV trials constitute 21% (or 41/197) of all regis-tered clinical trials, and involve the use of microor-ganisms that have been genetically engineered toinclude HIV genes. Almost all of the vectors are
viral, though the bacterium, Salmonella typhi, hasalso been used. The principle involves using themicroorganism to carry the HIV genes into the cellsof the vaccinated individual, where those genes areexpressed and rendered subject to host immuneresponses via presentation on the host cell-surfacein association with Major HistocompatibilityComplex (MHC) Class I molecules.
Thirty-seven of the 41 trials have been of indi-vidual vaccines, and four involved more than onetype of vaccine in this class. Collectively, 24 differ-ent vaccines have been tested in these trials, with27 Phase I, 11 Phase II, two Phase I/II and onePhase III trials initiated. RMVs are a relatively newapproach to the development of an HIV vaccine,reflected in the fact that just ten clinical trials havereached a conclusion, and that, excluding thecanarypox class of vaccines, all but one of the trialswere registered in or after 2003. It seems, however,that the primary emphasis of HIV trials has movedtoward this approach (5), given the recent high pro-file failures of recombinant-protein vaccines inPhase III trials, for example (81–83).
Of the concluded trials, seven of the ten werecompleted, two were terminated, and one was sus-pended.
Adenovirus
Twelve trials involving five adenovirus vaccines(based on the ‘common cold’ virus) are registered,constituting 29% of all the trials involving RMVs.This approach has received much attention, for anumber of reasons: adenoviruses induce mucosalimmunity, which should help prevent HIV infectionat genital/rectal sites; they infect dendritic cells, lead-ing to the efficient presentation of viral antigens; andthey elicit long-term humoral and cell-mediatedimmunity (84). They have also given successfulresults, including protection from HIV infection, instudies in several non-human species, including non-human primates, for example macaques (85) andchimpanzees (86–88). A combination approach,involving recombinant adenovirus-gp160 and gp120proteins, was also successful in chimpanzees, protect-ing them from even high-dose challenges of HIV afteronly a few immunisations (89–91).
Clinical work in this area is fairly advanced, withhalf of these trials being in Phase II, though two ofthem have been terminated. These terminated tri-als involved Merck’s V520 vaccine, which comprisesa recombinant Ad5 adenovirus containing the HIVgag, pol and nef genes. Despite being widely consid-ered by experts as “one of the most promising to betested on people so far” (92), trials of the vaccinewere terminated in September 2007, when aninterim analysis prior to the planned completion in2008 concluded that the vaccine simply wasn’tworking. It had failed to protect thousands of
Role of chimpanzees in AIDS vaccine research 411
Tab
le 2
: C
him
pan
zee
AID
S va
ccin
e tr
ials
lis
ted
in
th
e n
on
hu
man
pri
mat
e H
IV/S
IV v
acci
ne
tria
ls d
atab
ase
Ou
tcom
eP
rote
ctiv
e/im
mu
no-
ther
a-D
ate
Tri
al I
DT
itle
/des
crip
tion
(ref
eren
ce)
Inte
rven
tion
(s)
gen
ic?
peu
tic?
Not
es
Pas
sive
(e.
g. a
nti
bod
y-m
edia
ted
)
1988
NH
P .3
61F
ailu
re o
f hu
man
imm
unod
efic
ienc
y vi
rus
(HIV
) H
IVIG
—�
Pas
sive
ant
ibod
y, in
trav
enou
sim
mun
e gl
obul
in t
o pr
otec
t ch
impa
nzee
s ag
ains
t ex
peri
men
tal c
halle
nge
wit
h H
IV(1
46)
1990
NH
P .2
41A
ntib
ody-
med
iate
d in
vit
rone
utra
lisat
ion
of h
uman
N
/A—
�/�
Cha
lleng
e in
ocul
a m
ixed
wit
h N
HP
.243
imm
unod
efic
ienc
y vi
rus
type
I a
bolis
hes
infe
ctiv
ity
neut
ralis
ing
anti
body
pri
or t
o fo
r ch
impa
nzee
s(2
0)in
fect
ion
1991
NH
P .1
56P
reve
ntio
n of
HIV
-1 I
IIB
infe
ctio
n in
chi
mpa
nzee
s C
D4
Imm
un
oad
hes
in
—�
Solu
ble
CD
4 an
alog
ue, w
hich
by
CD
4 im
mun
oadh
esin
(23)
(CD
4-Ig
G)
com
pete
s fo
r C
D4
bind
ing
to t
he
CH
O-S
IVgp
120
HIV
gp1
20 e
nvel
ope
glyc
opro
tein
1992
NH
P .1
52.1
Pre
vent
ion
of H
IV-1
infe
ctio
n in
chi
mpa
nzee
s by
C
B1
anti
-V3
—�
Hyb
rid
mou
se–h
uman
ant
ibod
y to
NH
P .1
52.2
gp12
0 V
3 do
mai
n-sp
ecif
ic m
onoc
lona
l ant
ibod
y(1
5)th
e V
3 lo
op o
f H
IV-1
str
ain
IIIB
1999
NH
P .8
4P
oste
xpos
ure
imm
uno-
prop
hyla
xis
of p
rim
ary
mA
b B
4—
�M
onoc
lona
l ant
ibod
y di
rect
edis
olat
es b
y an
ant
ibod
y to
HIV
rec
epto
r co
mpl
ex(1
47)
agai
nst
HIV
rec
epto
r co
mpl
ex
Wh
ole
inac
tiva
ted
vir
us
1993
NH
P .2
04Im
mun
e re
spon
se o
f ch
impa
nzee
s af
ter
imm
unis
atio
nW
hole
inac
tiva
ted
HIV
-1 I
IIB
��
wit
h th
e in
acti
vate
d w
hole
imm
unod
efic
ienc
y vi
rus
(HIV
-1),
thre
e di
ffer
ent
adju
vant
s an
d ch
alle
nge
(37)
Rec
omb
inan
t p
rote
in
1988
NH
P .2
42H
uman
imm
unod
efic
ienc
y vi
rus
type
I c
halle
nge
of
rgp
120
��
Vac
cine
fro
m C
HO
cel
l lin
ech
impa
nzee
s im
mun
ised
wit
h re
com
bina
nt e
nvel
ope
glyc
opro
tein
gp1
20 (
148)
1989
NH
P.2
47C
halle
nge
of c
him
panz
ees
(Pan
trog
lody
tes)
gp
120
��
Vac
cine
pur
ifie
d fr
om H
IV-
imm
unis
ed w
ith
hum
an im
mun
odef
icie
ncy
viru
s in
fect
ed c
ell-l
ines
enve
lope
gly
copr
otei
n gp
120
(149
)St
rain
III
B
412 J. Bailey
Ou
tcom
e
Imm
un
o-P
rote
ctiv
e/ge
nic
?th
erap
euti
c?
Tab
le 2
: co
nti
nu
ed
Ou
tcom
eP
rote
ctiv
e/im
mu
no-
ther
a-D
ate
Tri
al I
DT
itle
/des
crip
tion
(ref
eren
ce)
Inte
rven
tion
(s)
gen
ic?
peu
tic?
Not
es
1990
NH
P.2
67P
rote
ctio
n of
chi
mpa
nzee
s fr
om in
fect
ion
by H
IV-1
gp
120
�V
acci
ne p
rodu
ced
in C
HO
cel
lsaf
ter
vacc
inat
ion
wit
h re
com
bina
nt g
lyco
prot
ein
�gp
120
but
not
gp16
0 (4
0)
gp16
0�
1991
NH
P.3
62Im
mun
isat
ion
of c
him
panz
ees
wit
h th
e H
IV-1
rg
p16
0�
—gl
ycop
rote
in g
p160
indu
ces
long
-last
ing
T-c
ell
mem
ory
(44)
1995
NH
P.1
93R
esis
tanc
e of
chi
mpa
nzee
s im
mun
ised
wit
h rg
p12
0�
/��
/�St
rain
SF
2, e
xpre
ssed
in C
HO
re
com
bina
nt g
p120
SF2
to c
halle
nge
by H
IV-1
SF2
(42)
cells
1996
NH
P.1
98P
rote
ctio
n of
MN
-rgp
120-
imm
unis
ed c
him
panz
ees
HIV
-1.M
N r
gp12
0�
�fr
om h
eter
olog
ous
infe
ctio
n w
ith
a pr
imar
y is
olat
e of
hu
man
imm
unod
efic
ienc
y vi
rus
type
1(4
1)
2001
NH
P.2
1P
rote
ctio
n fr
om s
econ
dary
hum
an im
mun
odef
icie
ncy
HIV
-1 W
6.1D
gp
120
��
Rec
ombi
nant
gp1
20 p
rote
in f
rom
vi
rus
type
1 in
fect
ion
in c
him
panz
ees
sugg
ests
the
st
rain
W6.
1Dim
port
ance
of
anti
geni
c bo
osti
ng a
nd a
pos
sibl
e ro
le
for
cyto
toxi
c T
cel
ls(1
50)
DN
A v
acci
nes
1997
NH
P.2
26P
rote
ctio
n of
chi
mpa
nzee
s fr
om h
igh-
dose
D
NA
vac
cine
enc
odin
g en
v, r
ev�
�he
tero
logo
us H
IV-1
cha
lleng
e by
DN
A v
acci
nati
on(7
1)an
d ga
g/po
l
1997
NH
P.2
02D
NA
vac
cina
tion
as
anti
-hum
an im
mun
odef
icie
ncy
pCM
N16
0 H
IV-1
.MN
env
-rev
��
DN
A p
lasm
id v
acci
ne e
xpre
ssin
g vi
rus
imm
unot
hera
py in
infe
cted
chi
mpa
nzee
s(1
51)
env
and
rev
Dat
e w
ere
cons
ider
ed, u
p to
and
inc
ludi
ng 1
1 N
ovem
ber
2007
. Rec
ords
of A
IDS
vac
cine
tria
ls i
n ch
impa
nzee
s w
ere
retr
ieve
d fr
om th
e N
onhu
man
Pri
mat
e H
IV/S
IV V
acci
neT
rial
s D
atab
ase
(htt
p://w
ww
.hiv
.lanl
.gov
/con
tent
/vac
cine
/hom
e.ht
ml).
Thi
s se
arch
pro
duce
d re
sult
s of
24
vacc
ine
tria
ls (a
ccou
ntin
g fo
r du
plic
ates
). C
olum
n fi
ve i
ndic
ates
whe
ther
the
vacc
ine
was
im
mun
ogen
ic i
n ch
impa
nzee
s (i
ndic
ated
by
a ch
eck/
cros
s fo
r ye
s/no
, or
a da
sh w
here
not
exp
lici
tly
mea
sure
d); c
olum
n si
x in
dica
tes
whe
ther
the
vacc
ine
was
eff
ecti
ve i
n pr
even
ting
HIV
inf
ecti
on o
r co
ntro
llin
g it
(ind
icat
ed b
y a
chec
k/cr
oss
for
yes/
no, o
r a
dash
whe
re n
ot e
xpli
citl
y m
easu
red)
. Int
erve
ntio
ns a
re s
how
n in
pla
in,
unde
rlin
ed, o
r bo
ld te
xt, t
o in
dica
te w
hich
vac
cine
s w
ere
subs
eque
ntly
test
ed i
n cl
inic
al tr
ials
, giv
en th
e ca
veat
that
the
freq
uent
poo
r qu
alit
y of
vac
cine
inf
orm
atio
n re
quir
es th
isto
be
an e
duca
ted
gues
s: P
lain
text
= n
o ev
iden
ce fo
und
for
subs
eque
nt te
stin
g in
hum
ans;
Und
erli
ned
text
= s
imil
ar b
ut n
ot i
dent
ical
to v
acci
ne te
sted
in
hum
ans
(e.g
. sam
epl
asm
id c
onta
inin
g sa
me
HIV
gen
e am
ong
othe
r ge
nes;
dif
fere
nt a
djuv
ant;
etc.
); B
old
text
= i
dent
ical
vac
cine
test
ed i
n hu
man
s.
Role of chimpanzees in AIDS vaccine research 413
Ou
tcom
e
Imm
un
o-P
rote
ctiv
e/ge
nic
?th
erap
euti
c?
Tab
le 2
: co
nti
nu
ed
Ou
tcom
eP
rote
ctiv
e/im
mu
no-
ther
a-D
ate
Tri
al I
DT
itle
/des
crip
tion
(ref
eren
ce)
Inte
rven
tion
(s)
gen
ic?
peu
tic?
Not
es
2000
NH
P.7
1T
hera
peut
ic im
mun
isat
ion
of H
IV-in
fect
ed
pCM
N16
0 H
IV-1
.MN
env
-rev
��
/�D
NA
con
stru
cts
expr
essi
ng M
N
chim
panz
ees
by u
sing
HIV
-1 p
lasm
id a
ntig
ens
and
stra
in E
nv a
nd R
ev p
rote
ins
inte
rleu
kin-
12 e
xpre
ssin
g pl
asm
ids
(72)
pCG
ag/P
olD
ecre
ase
in v
iral
load
s ob
serv
ed,
thou
gh t
rans
ient
Rec
omb
inan
t m
icro
bia
l va
ccin
esV
acci
nia
1987
NH
P.2
49E
ffec
t of
imm
unis
atio
n w
ith
a va
ccin
ia-H
IV
v-en
v5�
�R
ecom
bina
nt v
acci
nia-
env
viru
sre
com
bina
nt o
n H
IV in
fect
ion
in c
him
panz
ees
(152
)
1989
NH
P.2
44C
ell-m
edia
ted
imm
une
prol
ifer
ativ
e re
spon
ses
to
VV
160
Rec
ombi
nant
vac
cini
a-gp
160
viru
s H
IV-1
of
chim
panz
ees
vacc
inat
ed w
ith
diff
eren
t (V
V16
0)va
ccin
ia r
ecom
bina
nt v
irus
es(1
53)
VV
25�
/��
Rec
ombi
nant
vac
cini
a-p2
5 vi
rus
(VV
25)
VV
FR
ecom
bina
nt v
acci
nia-
F/3
´or
f vi
rus
(VV
F)
2000
NH
P.3
18M
ulti
-env
elop
e H
IV v
acci
ne s
afet
y an
d R
ecom
bina
nt v
acci
nia
viru
s-en
v�
—V
acci
nia
viru
s ex
pres
ses
mul
tipl
e im
mun
ogen
icit
y in
sm
all a
nim
als
and
chim
panz
ees
enve
lope
pro
tein
s(1
54)
Rec
omb
inan
t m
icro
bia
l va
ccin
esC
anar
ypox
1997
NH
P.2
25C
halle
nge
of c
him
panz
ees
imm
unis
ed w
ith
a A
LV
AC
-HIV
-1 v
CP
250
��
Rec
ombi
nant
vir
us e
xpre
sses
gp1
20re
com
bina
nt c
anar
ypox
-HIV
-1 v
irus
(155
)ga
g an
d pr
otea
se g
ene
prod
ucts
Mu
lti-
com
pon
ent
vacc
ines
1991
NH
P .1
59Im
mun
isat
ion
of c
him
panz
ees
conf
ers
prot
ecti
on
Who
le in
acti
vate
d vi
rus
agai
nst
chal
leng
e w
ith
hum
an im
mun
odef
icie
ncy
Pur
ifie
d re
com
bina
nt p
rote
ins
��
viru
s(4
6)Sy
nthe
tic
pept
ides
414 J. Bailey
Ou
tcom
e
Imm
un
o-P
rote
ctiv
e/ge
nic
?th
erap
euti
c?
Tab
le 2
: co
nti
nu
ed
Ou
tcom
eP
rote
ctiv
e/im
mu
no-
ther
a-D
ate
Tri
al I
DT
itle
/des
crip
tion
(ref
eren
ce)
Inte
rven
tion
(s)
gen
ic?
peu
tic?
Not
es
1998
NH
P .1
67F
ine
spec
ific
ity
of a
nti-V
3 an
tibo
dies
indu
ced
in
(i)
vCP
125/
gp16
0 co
mbi
nati
on�
�(i
) R
ecom
bina
nt c
anar
ypox
ch
impa
nzee
s by
HIV
can
dida
te v
acci
nes
(156
)A
LV
AC
(ex
pres
sing
gp1
60 M
N),
plus
gp1
60 (
MN
/LA
I st
rain
)(i
i) g
p160
plu
s V
3 pe
ptid
e bo
ost
(ii)
gp1
60 M
N/L
AI
stra
in p
lus
synt
heti
c V
3 pe
ptid
e
1998
NH
P .1
41V
acci
ne p
rote
ctio
n ag
ains
t a
hete
rolo
gous
, P
rim
e: r
ec. a
deno
viru
s-gp
160
��
non-
sync
ytiu
m-in
duci
ng, p
rim
ary
hum
an
(MN
)im
mun
odef
icie
ncy
viru
s(9
0)B
oost
: gp1
20 p
rote
in (
SF2)
2005
NH
P .4
65R
eplic
atin
g ra
ther
tha
n no
n-re
plic
atin
g ad
enov
irus
–P
rim
e: A
d5 a
nd A
d7�
—Se
quen
tial
pri
min
g im
mun
isat
ions
hum
an im
mun
odef
icie
ncy
viru
s re
com
bina
nt
aden
ovir
uses
, bot
h re
plic
atio
nw
ith
diff
eren
t se
roty
pes
of
vacc
ines
are
bet
ter
at e
licit
ing
pote
nt c
ellu
lar
com
pete
nt a
nd d
efic
ient
aden
ovir
us e
nv-r
ev r
ecom
bina
nts,
im
mun
ity
and
prim
ing
high
-tit
re a
ntib
odie
s(9
1)an
d bo
osti
ng w
ith
olig
omer
ic
Boo
st: o
ligom
eric
gp1
40 d
elta
V2
gp14
0 de
lta
V2
(str
ain
SF16
2)
Dat
e w
ere
cons
ider
ed, u
p to
and
inc
ludi
ng 1
1 N
ovem
ber
2007
. Rec
ords
of A
IDS
vac
cine
tria
ls i
n ch
impa
nzee
s w
ere
retr
ieve
d fr
om th
e N
onhu
man
Pri
mat
e H
IV/S
IV V
acci
neT
rial
s D
atab
ase
(htt
p://w
ww
.hiv
.lanl
.gov
/con
tent
/vac
cine
/hom
e.ht
ml).
Thi
s se
arch
pro
duce
d re
sult
s of
24
vacc
ine
tria
ls (a
ccou
ntin
g fo
r du
plic
ates
). C
olum
n fi
ve i
ndic
ates
whe
ther
the
vacc
ine
was
im
mun
ogen
ic i
n ch
impa
nzee
s (i
ndic
ated
by
a ch
eck/
cros
s fo
r ye
s/no
, or
a da
sh w
here
not
exp
lici
tly
mea
sure
d); c
olum
n si
x in
dica
tes
whe
ther
the
vacc
ine
was
eff
ecti
ve i
n pr
even
ting
HIV
inf
ecti
on o
r co
ntro
llin
g it
(ind
icat
ed b
y a
chec
k/cr
oss
for
yes/
no, o
r a
dash
whe
re n
ot e
xpli
citl
y m
easu
red)
. Int
erve
ntio
ns a
re s
how
n in
pla
in,
unde
rlin
ed, o
r bo
ld te
xt, t
o in
dica
te w
hich
vac
cine
s w
ere
subs
eque
ntly
test
ed i
n cl
inic
al tr
ials
, giv
en th
e ca
veat
that
the
freq
uent
poo
r qu
alit
y of
vac
cine
inf
orm
atio
n re
quir
es th
isto
be
an e
duca
ted
gues
s: P
lain
text
= n
o ev
iden
ce fo
und
for
subs
eque
nt te
stin
g in
hum
ans;
Und
erli
ned
text
= s
imil
ar b
ut n
ot i
dent
ical
to v
acci
ne te
sted
in
hum
ans
(e.g
. sam
epl
asm
id c
onta
inin
g sa
me
HIV
gen
e am
ong
othe
r ge
nes;
dif
fere
nt a
djuv
ant;
etc.
); B
old
text
= i
dent
ical
vac
cine
test
ed i
n hu
man
s.
Role of chimpanzees in AIDS vaccine research 415
Ou
tcom
e
Imm
un
o-P
rote
ctiv
e/ge
nic
?th
erap
euti
c?
volunteers from HIV infection, and also to reduceHIV levels in people already infected. Disturbingly,more HIV infections were present in those who hadbeen given the vaccine, as compared to those giventhe placebo (24 versus 21, respectively), with thosewho had been in the trial longer and who hadreceived more injections faring even worse, with 19cases of HIV infection after vaccination versus just11 after placebo treatment (93, 94).
As this was the first viral-recombinant vaccine toreach this stage of clinical trials, and the first toexamine cell-mediated immunity alone in humans(53), some believe that it raises questions aboutwhether the use of RMVs can be successful at all,particularly as vaccines based on adenovirus haveappeared to be the most immunogenic in terms ofthe percentage of human responders and the leveland duration of T-cell responses (95).
Adeno-associated virus
Just one trial was identified involving recombinantadeno-associated virus (AAV), which was registeredin 2007, although it commenced in 2003. ThisPhase I trial has been completed, and evaluated anAAV containing clade C gag, pro, and rt HIVsequences.
Vaccinia
Of 40 single-intervention recombinant microbialvaccine trials, eight, involving seven vaccinia-virusbased interventions, were identified, though justone trial has been completed. All but two are PhaseI trials, with one trial at Phase I/II and another atPhase II.
Three trials involving recombinant vaccinia vac-cines in chimpanzees were identified in the NHPVTdatabase. Although all the vaccines were immuno-genic, the two trials that took place in the 1980s didnot show protection from HIV infection. The othertrial took place more recently in 2000, but onlyassessed immunogenicity.
Modified Vaccinia Ankara virus (MVA) forms thebasis of many recombinant vaccinia approaches to anHIV vaccine, because of its high degree of attenuationand consequent good safety profile. Initial results inhuman trials, however, have been disappointing, withcell-mediated immunity being elicited in only a smallminority of individuals (96), despite promising resultsin macaques (5). Human trials that include MVA vac-cines as part of a prime–boost strategy have also beendisappointing (6).
Canarypox
Vectors based on the canarypox virus constitute thebiggest proportion of trials involving RMVs — alto-
gether around a third of the total (13/41, or 32%), fiveof which have progressed to Phase II; the remainderare Phase I trials. These trials involved four differentvaccines, all based upon the ALVAC vector developedby Sanofi-Pasteur (based on an attenuated strain ofcanarypox). In principle, these vectors are highly fit-for-purpose: they replicate only in the cytoplasm ofinfected cells (minimising the risk of integration withthe host genome and any ensuing problems); replica-tion is restricted; and they are sufficiently safe andwell tolerated in humans (97, 98). Further, they canaccommodate large gene insertions (99), and they canstimulate both humoral and cell-mediated immuneresponses of long duration in humans (100–102).
An early Phase I/II trial ended in disappointment,however, when a gp160 vaccine (ALVAC-HIV)failed to enhance both humoral and cell-mediatedimmune responses (103). Looking at the register ofclinical trials (Table 1), further failures with otherALVAC trials appear to have followed. Focus seemsto have shifted to other approaches, signalled by thelow number of trials registered in recent years(compared to 1999–2001, for example). This is true,not just for trials solely involving canarypox, butalso for the many trials of AIDS vaccines involvingrecombinant canarypox in combination with otherapproaches such as the use of DNA and recombi-nant proteins. In addition, it has been reported thatfive different canarypox vaccines have been testedin around 11,500 volunteers (5). Though well toler-ated, these vaccines did not induce durable immuneresponses, and were immunogenic in fewer than20% of the subjects (104).
Canarypox vaccines have also been tested in chil-dren, with similarly disappointing results. Forexample, the vCP205 and vCP1452 vaccines weregiven to very young infants of HIV+ mothers; again,they were well tolerated, but produced humoral andcell-mediated immune responses either not at all, orof a very low magnitude (105). Comparison withchimpanzee vaccinations is difficult, as just onesuch trial is listed in the NHPVT database, involv-ing three animals. In this instance, the vCP250 vac-cine was immunogenic, and protected one of thetwo experimental animals from cell-associated viralchallenge. It did not, however, protect this chim-panzee against subsequent infection with cell-freeHIV (Table 2).
As mentioned previously, many trials have usedcanarypox in combination with other vaccine candi-dates — though this has not resulted in an improve-ment in efficacy. For example, vCP1452 has beenadministered with an AIDSVAX B/B boost toinfants, but enthusiasm for further trials was lim-ited due to ‘modest immunogenicity’ (70).
Others
Two clinical trials involved the use of VenezuelanEquine Enceph alitis alphavirus (VEE) as a vector.
416 J. Bailey
Both Phase I trials, they assessed the vaccineAVX101, which contains the HIV gag gene as animmunogen. Another trial, registered in 2003 butnot yet recruiting participants, proposes to evaluatea vaccine based on recombinant Salmonella typhicontaining the HIV gp120 gene.
Three clinical trials, all registered relativelyrecently (2004–2006), involved more than one typeof RMV. Two of the three trials investigated combi-nations of vaccinia-based (MVA) and fowlpox-basedvaccine pairs, each containing the env/gag andtat/rev/nef HIV genes. The status of the earlier ofthe two trials is ‘no longer recruiting,’ though thedetails state that all vaccinations were discontinuedin Novem ber 2006, and the other trial has been sus-pended. The third trial will assess a ‘prime–boost’intervention involving an initial DNA plasmid vac-cine ‘prime’, followed by a Modified VacciniaAnkara (MVA) ‘boost’ (this approach is described inmore detail later in this review).
Autologous cells
Dendritic cells are one of the first ports-of-call forthe virus upon infection. They are locally infectedat the entry site of the virus, before proceeding tothe lymph nodes where they infect CD4+ T-cells —the principal target of the virus, the attrition ofwhich leads to AIDS. Consequently, dendritic cellsare central to the induction of the immune responseto HIV infection, though their response is known todecline with time (106–109).
With this in mind, six trials have been registeredthat involve two types of autologous-cell approachto therapeutic HIV vaccination: five with dendriticcells, and the other with T-cells. The former strat-egy involves harvesting a patient’s own dendriticcells and loading them in vitro with HIV peptideantigens or inactivated autologous virus. The latterT-cell based vaccine is prepared from autologous T-cells, which have proliferated following exposure torecombinant CD4. The cells are then introducedback into the patient, in the hope that they can bet-ter activate immune responses that can control theinfection. Early results in humans are consideredpromising, at least against the same viral strainused to produce the cell-based vaccine (110), thoughthis must be interpreted with caution, as any effi-cacious vaccine must elicit immune responsesagainst diverse strains of HIV.
No chimpanzee trials of this vaccine type werelisted in the NHPVT database, though the immuno-genicity in chimpanzees of dendritic cells pulsedwith test antigens has been reported in the scien-tific literature, with somewhat equivocal results(111, 112), and a T-cell vaccine for hepatitis C hasbeen tested in chimpanzees, which elicited immu-nity against heterologous hepatitis C virus (HCV;113).
Multi-component vaccines and prime–booststrategies
Due to negative results in many trials involving sin-gle vaccines of all types, much focus has shiftedtoward the development of multi-component vac-cines, in so-called ‘prime–boost’ strategies. Thistype of intervention aims to enhance the immuneresponse to a particular antigen, and to induce boththe humoral and cell-mediated arms of the immuneresponse by administering it in successive, butslightly different, ways — especially when usingjust one route/vaccine type has not proved suffi-ciently immunogenic. The rationale is to ‘prime’ theimmune system with the first antigen (for example,a DNA vaccine or recombinant adenovirus orpoxvirus), and then to ‘boost’ the immune responseto it by using, for example, another RMV or protein.
Fifty clinical trials were identified in this category(Figure 5), with the most prevalent combinationsbeing canarypox–protein (15 trials), adenovirus–DNA(11 trials) and vaccinia–protein (7 trials). Given therelatively recent nature of this type of approach, themajority of the trials are Phase I trials (31/50), withjust seven Phase II and two Phase III trials. One ofthe Phase II trials, involving a canarypox–lipopeptidevaccine (ALVAC HIV-1433 and LIPO-6T), was termi-nated, and a recent publication revealed that HIV-specific CD4+ T-cell responses did not change inimmunised patients relative to controls, that the vac-cination had only a transient effect on interferon-gamma-producing CD8 responses, and that the viralrebound after treatment interruption was similar inimmunised patients and controls (114). The Phase IIItrial, involving a canarypox–inactivated virus vaccine(vCP1452 and Remune), was registered in 2000 andhas been completed (without success), and the othertrial, involving a canarypox–protein vaccine combina-tion (vCP1521 and AIDSVAX gp120 B/E), com-menced in 2003 and is no longer recruiting.
Despite this Phase II termination and the lack ofreported success surrounding the Phase II trials,much hope is held in some quarters for this strat-egy, largely based on pre-clinical studies in mon-keys, where prime–boost vaccines are often morepotent than either vaccine alone (55). The NHPVTdatabase lists four chimpanzee trials of multi-com-ponent vaccines, one of which tested two differentvaccine combinations. All five combinations wereimmunogenic. One of the trials (NHP .465), involv-ing an adenovirus prime and an oligomeric gp140boost, did not assess protection from infection, butall the other vaccines demonstrated protection,except one, which comprised a vCP125/gp160 com-bination (trial NHP .167). In addition to those stud-ies registered with the NHP database, Girard et al.(47) reported the protection of chimpanzees fromHIV infection following immunisation with “a vari-ety of HIV-1 immunogens — followed by rgp160and V3 peptides”, including combinations of enve-
Role of chimpanzees in AIDS vaccine research 417
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lope antigens. This all contrasts with findings inhumans, however, where “observations in earlyphase clinical trials in humans have not been prom-ising”, due to adverse reactions and lack of diversityin the immune response (115).
Naturally, not all the vaccines tested in chim-panzees have provided protection against HIV chal-lenge. One of the vaccine combinations tested byGirard et al. (47), for example, described a combi-nation strategy involving recombinant gp160–canarypox and recombinant gp160 protein, thatfailed, although the low dose of the vaccine was pos-tulated as a factor.
Summary and Discussion
To date, 85 candidate AIDS vaccines have beentested in 197 clinical trials, comprising several maintypes — from inactivated virus vaccines throughDNA plasmids to recombinant proteins and viruses.Just 12% of these trials have reached Phase II, onlyseven (3.5%) have reached Phase III, and alto-gether, 18 trials were prematurely terminated.None has been successful.
Early optimism has transformed into a realisa-tion that we are decades away from even a partiallyeffective vaccine in humans. The monumentalfinancial and human resources allocated to vaccinedevelopment have resulted in dozens of safe andeffective vaccines only for chimpanzees and mon-keys with laboratory-induced infections. Hope thatthe use of NHPs will lead to the successful develop-ment of a vaccine for humans is tempered by therecent, high-profile failures of the AIDSVAX andV520 (Merck) candidates in extensive and late-stageclinical trials. Notably, the latter increased the riskof HIV infection compared to the placebo — and itis not alone in this respect: previously, gp120-basedvaccines increased the risk that vaccinated peoplewould develop an infection or progress to AIDSpost-infection (116).
Furthermore, the limited critical appraisal to dateof the favoured SIV/chimeric SIV–Human Immuno -deficiency Virus (SIV/SHIV)-macaque model, hasbeen unfavourable (35, 53, 56, 117–121), stimulatinga desire for models of greater relevance. While somescientists associated with chimpanzee research advo-cate a resumption of their use, such use must beobjectively and independently evaluated.
Poor performance of the chimpanzee modelin the development of AIDS vaccines
This analysis expands on previous data that under-lined the poor performance of chimpanzees as mod-els in HIV/AIDS research, evidenced by a largenumber of negative opinions and comments towardit and by the significant withdrawal of NIH funding
for it. The evidence provided, based on a compari-son of human and chimpanzee responses to AIDSvaccines, gives further argument against a returnto chimpanzee-use in this field.
Contrary to claims that chimpanzees play a “crit-ical role in the testing of potential [HIV] vaccines”and that they “are still important for testing vac-cines aimed at preventing HIV-1 infection or reduc-ing the virus load in infected individuals”(14), thisreview shows that neither claim has any scientificfoundation. Many vaccines of many types have beentested in chimpanzees prior to clinical trials, andtheir correlation to, and predictive nature for, thehuman response is demonstrably poor. Chimp -anzees have been protected from HIV infection pas-sively via the transfer of antibodies (both pre- andpost-exposure), which prompted the (now highlyunlikely) suggestion that cell-mediated immunity isnot necessary. Passive protection has also beeninduced by a soluble CD4 analogue. Neitherapproach has been successful in humans. Atten -uated vaccines have provided protection in chim-panzees, but have not been tested clinically due tosafety concerns. Inactivated-virus vaccines havedisappointed clinically, and while results were sim-ilarly negative in chimpanzees, these results were oflittle relevance and did not prevent inactivated-virus vaccines from progressing to clinical trials.Negative results with recombinant protein vaccinesin chimpanzees (Table 2) also did not stop thesevaccines progressing to further testing and clinicaltrials (122).
While RMVs have been disappointing in humans,including the Phase III AIDSVAX trials, many(excluding a couple of early efforts) provided protec-tion from HIV infection in chimpanzees. Clinical trialsuccess with peptide and lipopeptide vaccines has notbeen reported, despite prior evidence of potent andpersistent cell-mediated immune responses in chim-panzees. Both preventive and therapeutic DNA vacci-nation have been successful in chimpanzees.Optimism for success in humans was high, but poorimmunogenicity has led to recent disparaging com-ments. Recombinant adenovirus vaccines haveelicited protection from HIV infection in chim-panzees, both alone and in combination with recom-binant HIV proteins. However, the situation inhumans may be grave, with possibly “the most prom-ising [vaccine] tested on people so far”, in the form ofMerck’s V520 vaccine, not only ending in the termi-nation of its Phase IIb trial, but increasing the risk ofHIV infection for its recipients.
Due to the diminished use of chimpanzees inpre-clinical testing for reasons discussed above,some types of vaccines have not been widely testedin chimpanzees. Immunogenicity has been demon-strated in chimpanzees with vaccinia-based vac-cines, however — which is true in only a smallminority of humans in clinical trials so far.Similarly, canarypox vaccines have induced pro-
Role of chimpanzees in AIDS vaccine research 419
tection from cell-associated (but not cell-free)virus challenge in chimpanzees, but several vec-tors have been immunogenic in a small proportionof clinical-trial volunteers, including children,even as part of prime–boost regimens — and thenonly poorly so. Some prime–boost vaccines, involv-ing a variety of immunogens, have proven positivein chimpanzees, again in contrast to humans, inwhich the results have been disappointing, repletewith adverse reactions and lack of diversity in theimmune response.
Problems with the chimpanzee model:Reasons for its lack of relevance
Researchers continue to rely on results largely frommacaques infected with SIV or SHIV (an SIV/HIVhybrid), despite important differences between SIV-infected macaques and HIV-infected humans (53,117). Significant disparities exist in virulence,pathology, genetics, protein function, infection andhost response (118). Two recent reviews statedthat, “efficacy of HIV-1 based vaccines cannot bedirectly evaluated in the SIV model” (119) and that,“this has not proven a practical animal model forstudying vaccines” (35), the latter citing significantsupporting evidence (56, 121, 122). A 2007 reviewstated, “When it comes to testing HIV vaccines,only humans will do” (53); another cited, “the per-sistent view held by many that there is no predic-tive animal model for HIV infection in humans”(123), and another that, “No animal models faith-fully reproduce... HIV-1 infection and disease inhumans, and the studies of experimental vaccinesin animal models... have yielded disparate results”(124).
Yet the rhesus macaque became the model ofchoice following the discovery in 1987 that SIVcaused an AIDS-like disease in these animals (125).It replaced the chimpanzee, widely used in AIDSresearch for several years previously but which had“had problems from the get-go” (125) — vis-à-vispracticality (the significant costs of using and main-taining chimpanzees, including user’s fees of$50,000+ per animal), statistical significance (fewanimals could be used in each experiment, givingunreliable results), and species differences (HIVinfection rarely progresses to AIDS-like illness inchimpanzees) “undermining the model’s reliabil-ity” (125). The latter problem of scientific unrelia-bility is, from a human perspective, most worrying.If years of chimpanzee use in HIV/AIDS researchhave not led to tangible progress and improvementsclinically, then they represent a waste of limitedresources and have done little to alleviate humansuffering, as there is still no AIDS vaccine and noneis imminent. A brief summary of the known differ-ences between human and chimpanzee HIV infec-tion and ensuing pathology may explain why.
Chimpanzees have higher baseline levels of CD8+
T-cells and a higher ratio of CD8+/CD4+ T-cells,and their percentage of beta-chemokine-positiveCD8+ T-cells and natural killer (NK) cells is signif-icantly higher than in uninfected humans.Chimpanzees do not typically produce increasednumbers of these cells following HIV infection,unlike humans (126). As these are the cells thatattempt to control infection, and the latter are thecells infected by HIV-1 and subsequently destroyedby the virus, this is critical. Unlike in humans, it isdifficult to routinely isolate HIV from the plasmaand sera of infected chimpanzees (127), and chim-panzee CD4+ cell numbers do not drop dramaticallyover the course of HIV infection, with remarkablyfew exceptions. Instead, detectable plasma HIVdecreases and eventually becomes undetectable(117). With perhaps only one exception, HIV infec-tion of chimpanzees does not result in a significantdecline in CD4+ T-cell levels, immunodeficiencyand AIDS-like illness, as in humans. The exceptionwas Jerom (‘Chimpanzee C499’), who was infectedwith three different isolates of HIV-1 over ten yearsand suffered a progressive decline in CD4+ T-cellsand developed AIDS-like symptoms, caused by aquasispecies of HIV that had mutated to becomemore pathogenic (128). Notably, Jerom’s blood,though it caused a similar decline in CD4+ T-cellsin other chimpanzees transfused with it, did notcause them to develop a similar disease (129).
These differences, difficulties, and the lack of avaccine led many scientists to conclude that chim-panzees should have no place in the quest for anAIDS vaccine. In 1994, the Handbook of LaboratoryAnimal Science called primate models of AIDS“unsuccessful” (130). The NIH AIDS ResearchProgram Evaluation Task Force cited the “limitedutility of the chimpanzee model” and recommended“redirecting monies currently expended in the lessrelevant chimpanzee model” (131). The latter wasput into practice: AIDS-related chimpanzee studiesfell from almost 30 studies in 1998 to four in 2005.Thomas Insel M.D., former director of the YerkesRegional Primate Center, noted that 15 years ofwork in chimpanzees has produced little data rele-vant to humans, stating “I can’t tell you what it isthat those [chimpanzee] studies have given us thathas really made a difference in the way we approachpeople with this disease [HIV/AIDS]” (132); and areview article in 2000 opined “Defending the use-fulness of the chimpanzee as a model for HIVresearch has not only become a difficult task, butalso a controversial one” (133).
These realisations came too late. At least 198chimpanzees were deliberately infected with HIVprior to 1997 (134), and around 1,300 chimpanzeesare currently in US laboratories, due in large partto over-breeding for AIDS research in anticipationof their use in this area, and despite a breedingmoratorium being in place for the past decade.
420 J. Bailey
Ethical issues associated with chimpanzee use
Ethics must be considered alongside scientific rele-vance, because of the cost of chimpanzee use, andbecause chimpanzees are a ‘special case’, testified toby public and scientific opinion, and policies andlaws in the US and throughout the world. The pas-sage of the CHIMP (Chimpanzee Health Improve -ment, Maintenance and Protection) Act in the USAin 2000, as well as the fact that many countries banor restrict the use of great apes, acknowledges a dif-ferent moral status for chimpanzees. Both scien-tists and the public acknowledge that chimpanzeeshave advanced cognitive abilities, and social andemotional needs. They are capable of reasonedthought, abstraction, generalisation and symbolicrepresentation; have a concept of self; exhibit abroad range of emotions; experience mental as wellas physical pain; and can be taught to communicatein human languages such as American Sign Lang -uage, and demonstrate complex nonverbal commu-nication patterns among themselves (135–142). Incaptivity, they show a range of behavioural abnor-malities and measurable signs of distress (psy-chopathology; 143, 144). The widely-respectedresearcher and advocate for chimpanzee welfare,Jane Goodall, stated in a letter to Science that, “Itis their humanlike behaviours that most fascinatepeople: their tool-using and making abilities, theclose supportive bonds among family members…and their complex social interactions — the cooper-ation, the altruism, and the expression of emotionslike joy and sadness” (145).
Conclusions
The evidence presented in this study includes:
— substantial differences between chimpanzee andhuman responses to HIV infection and thecourse of the disease;
— expert opinion;
— past failures as a vaccine model;
— progression of vaccines to clinical trials despitenegative results in chimpanzees;
— increasing knowledge of chimpanzees’ cognitiveand emotional capacities; and
— increased ethical issues surrounding chim-panzee research.
From this evidence, it is concluded that chim-panzees have no justifiable role in AIDS vaccineresearch and testing. Advocating the resumption oftheir use defies the burden of scientific evidence ofrepeated failures involving their use. If chim-panzees were not reliable, predictive and fit for pur-pose from 1990 to 2008, what justification is therefor a resumption of their use? A 2006 review ofAIDS vaccine testing, when referring to chim-
panzee trials of inactivated-virus and DNA vac-cines, concluded “it proved difficult to examine theeffect of these vaccines, due to the general lack ofclinical progression to immunodeficiency in thisanimal model and the prohibitive cost of theseexperiments” (7).
Some twenty years after chimpanzees were themainstay of AIDS vaccine testing, an efficaciousvaccine for human use remains unavailable and notimminent. The use of chimpanzees has largely beenabandoned for scientific and cost–benefit reasons.As millions of humans continue to become infectedor die each year, the continued use of chimpanzeesin AIDS research is scientifically unwise and ethi-cally unjustifiable.
Received 03.04.08; received in final form 27.06.08;accepted for publication 28.06.08.
Acknowledgements
Jarrod Bailey was the sole author of this manu-script and was responsible for its conception,research and preparation. The work herein has notbeen presented anywhere else prior to this publica-tion. Sincere gratitude is expressed to the NewEngland Anti-Vivisection Society for funding theproject, and to Theodora Capaldo and all the otherswho offered their time and expertise in reviewingthe manuscript during its preparation. There are noconflicts of interest.
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