Thumbi’Ndung’u,’BVM,’PhD’ KwaZulu8Natal’Research’Ins@tute...

Thumbi  Ndung’u,  BVM,  PhD  KwaZulu-­‐Natal  Research  Ins@tute  for  Tuberculosis  and  HIV  (K-­‐RITH)  

and  HIV  Pathogenesis  Programme  Nelson  R.  Mandela  School  of  Medicine  

University  of  KwaZulu-­‐Natal  

Biomedical  HIV  Preven2on  Forum,  Harare,  Zimbabwe,  29  November  2015  

HIV  vaccine  research  and  implica@ons  for  HIV  control  in  Africa  

•  The  need  for  an  HIV  vaccine  

•  Past  vaccines:  successes  and  challenges    •  Challenges  and  barriers  to  an  HIV  vaccine    •  Overcoming  the  challenges-­‐  reasons  for  op>mism  

 -­‐  Recent  work  on  the  CD8+  T  cell  immune  responses    -­‐  Neutralizing  and  other  an>body  func>ons  

 •  The  need  for  involvement  of  African  scien>sts  and  its  young  people  

Presenta@on  outline  

Clinical  trial  evidence  for  preven@ng  sexual  HIV  transmission  

Efficacy  

Study   Effect  size  (CI)  

Medical  male  circumcision    (Orange  Farm,  Rakai,  Kisumu)   54%  (38;  66)  

HIV  Vaccine    (Thai  RV144)  

31%  (1;  51)  0% 10 20 30 40 50 60 70 80 90 100%

STD  treatment    (Mwanza,  Tanzania)    

42%  (21;  58)  

39%  (6;  60)  Microbicide  (South  Africa)  

PrEP for MSMs (Americas, Thailand, South Africa) 44%  (15;  63)  

Treatment  for  preven>on  (Africa,  Asia,  Americas)   96%  (73;  99)  

PrEP  for  heterosexuals  (Botswana  TDF2)   63%  (21;  48)  

PrEP  for  discordant  couples  (Partners  PrEP)   73%  (49;  85)

Modified  from  Abdool  Karim,  2013  Lancet  

Poten@al  Impact  of  an  HIV  Vaccine  

John  Stover  et  al.  Health  Aff  2007;26:1147-­‐1158  

30%  efficacy,  20%  coverage  

50%  efficacy,  30%  coverage  

70%  efficacy,  40%  coverage  

6 million

17  million  

28  million  

Total  new  infec@ons  averted  by  an  HIV  vaccine  

between  2015  -­‐  2030  

“….but  what  renders  the  Cow  Pox  so  extremely  singular  is  that  the  person  who  has  been  thus  affected  is  for  ever  acer  secure  from  the  infec@on  of  the  Small  Pox…”    Edward  Jenner,  1798.    

A  sterilizing,  durable  vaccine  is  a  powerful  public  health  tool  

Vaccines  take  @me  to  develop…  

Vaccine   Discovery  of  causa@ve  agent  

Vaccine  Developed  for  Human  Use  

Years  to  Vaccine    

H.  Influenzae-­‐B     1892     1985     93    

Herpes  (HSV-­‐1)     1919     Not  available     >90    

Pertussis     1906     1926     20    

Polio*     1909     1954     47    

Yellow  Fever     1900     1935     35    

Influenza     1933     1945     12    

Measles     1911     1957     46    

Modified  from  H.  Markel,  NEJM,  August  25,  2005  

*In  the  1930s,  two  experimental  polio  vaccines  failed  because  they  were  determined  to  be  unsafe,  and  polio  vaccines  were  almost  abandoned.  

What  is  a  vaccine  ?  

A  vaccine  is  a  substance  that  teaches  the  body’s  immune  system  to  recognize  and  protect  against  a  disease  caused  by  an  infec>ous  agent    (e.g.  virus  or  bacterium).  

B  cell  

Th  

Viral  protein  

Th  

CTL  

New  virus  assembly  

HLA-­‐1  

HIV  

Infected  cell  

Neutralizing    an@bodies  

Modified  from  Walker  and  Burton  (2008),  Science.    

How  might  HIV  vaccines  work?      

Viral  load    copies/ml  

Time  HIV  

Viral  load    copies/ml  

HIV  

Viral  load    copies/ml  

HIV  

Goals  of  a  prophylac@c  HIV  vaccine  

Induces  immunity  that  allows  transient    HIV  replica>on  

Induces  sterilizing  immunity-­‐  no  infec>on    upon  exposure  

Induces  immunity  that  greatly  weakens  the  virus:  no  disease  and  no  transmission                

Disease/transmission  threshold  

Time  

Time  

How  is  a  vaccine  developed?  

Discovery   Vaccine  design  

Preclinical  research   Clinical  trials  

Stages  of  Clinical  Trials  

12  to  18  months  Small  group  of  healthy,  HIV  nega>ve  par>cipants  to  test  safety  

Up  to  2  years  Hundreds  of  HIV  nega>ve  par>cipants  to  test  safety  and  immune  responses  

3  to  4  years  Thousands  of    par>cipants  at  risk  to  test  safety  and  efficacy  

PHASE  I   PHASE  II   PHASE  III  

HIV  vaccine  efficacy  trials  

No

NOTE: Phambili (HVTN 503) began to explore a regimen similar to STEP in South Africa (not included).

     Why  haven’t  these  vaccines  worked?  Scien@fic  Obstacles  

•  The  natural  immune  response  to  HIV  infec>on  does  not  eliminate  the  virus  (we  don’t  understand  what  cons>tutes  protec>ve  immunity)  

   •  Enormous  sequence  variability.  We  do  not  know  how  to  construct  an  immunogen  to  cover  this  sequence  variability  

•  Immune  responses  induced  by  vaccina>on  are  generally  weak  (low  magnitude  and  breadth),  no  neutraliza>on  

Viral  diversity-­‐  arguably  the  most  significant    challenge  in  HIV-­‐1  vaccine  development  

Ndung’u  and  Weiss,  2012,  AIDS  Adapted  with  permission  from  Korber  et  al,  2001,  Br.  Med.  Bull  

Case  studies  of:    •  Overcoming  diversity  through  mosaic  immunogen  designs  

•  Improving  immunogenicity  through  novel  vectors  

•  Novel  designs  for  neutralizing  an>bodies    

How  do  we  overcome  scien@fic  challenges  in  HIV  vaccine  development?  

Input: Single clade or M group

Mosaic antigens can be designed to increase coverage of HIV diversity

Fischer  et  al.  Nat.  Med.  2007;  13:100-­‐106  

The  Ad26  mosaic  vaccine  yielded  many  more  Gag,  Pol,  and  Env  (A)  epitope-­‐specific  T  lymphocyte  responses  as  well  as  (B)  numbers  of  epitope  response  regions  to  PTE  pep>des  than  did  the  Ad26  M  consensus,  clade  B  +  clade  C,  or  op>mal  natural  clade  C  vaccines  

Expanded  breadth  by  mosaic  compared  with  

consensus  or  natural  Gag/Pol/Env  an@gens  in Rhesus Monkeys

Barouch  et  al.  Nat.  Med.  2010;  16:319-­‐323  

Novel  vectors  –such  as    replica@ng  CMV  may  overcome  the  kine@c  mismatch  problem!  

52%   (25/48)   of   CMV   vector-­‐vaccinated   RM,   upon   infec@on,   manifested  immediate  virologic  control  and  eventual  viral  clearance  in  some  for  >52  weeks.  

Barouch  and  Picker,  2014,  Nat  Rev  Micro  

Hansen  et  al,  Science  2013  

Plausibility  of  approach-­‐  even  berer  with  recent  discovery  of    vectors  that  violate  the  CD8+  epitope  recogni@on  paradigm  

Immunogens  to  prevent  escape  or  arenuate  the  virus  tat

3’LTR

5’ LTR gag

pol env

vif

vpr

vpu

nef

3’ LTR

rev

Time post HIV infection

Vira

l fitn

ess

Mann  and  Ndung’u,  2015,  Virol  Journ    

Prototype  broadly  nAbs:  binding  regions  

A.  Ward  &  C.  Corbaci  

Gray  -­‐  Gp120    Red-­‐              the  CD4  binding  site  on  gp120  

Image  credit:  NIAID/NIH  Vaccine  Research  Center  

Green  &  Purple  –    the  VRC01  an>body  alached  to  the  CD4  binding  site  

VRC01:  a  bnAb  to  the  CD4bs  on  gp120  

•  Discovered  in  an  individual  HIV-­‐1  infected  for  >15  yrs,  who  maintained  virologic  control  on  no  ART    

•  Developed  by  John  Mascola  &  colleagues  at  the  Vaccine  Research  Center  of  the  Na>onal  ins>tutes  of  Health  

VRC01  is  broadly  neutralizing  

Panel of 190 Diverse Viral Isolates

Rational design of envelope identifies broadly neutralizing human monoclonal Antibodies to HIV. Science. 2010

Vector  Mediated  Gene  Delivery  of  Broadly  Neutralizing  An@bodies:  AAV1-­‐PG9  Prototype  

Slide  modified  courtesy  of  P  Johnson  and  F  Priddy  

•  Mosaic Antigens: Ad26, MVA, gp140 (J&J) (~ PhIIb 2018) •  Conserved-Mosaic Antigens: chAd, MVA (PhIIb 2019 – 2020)

•  HIV ENV trimers •  ENV epitopes •  Env DNA

•  Attenuated VSV •  Vaccinia virus Tiantan •  Sendai •  Adeno 4

•  CMV •  CDV •  VSV •  Pox: NYVAC •  RepliVax (Flavi)

Improving RV-144: CMI + non-neutralizing Ab

Improve the breadth of vaccine

Candidates to Elicit bnAbs

Replicating Vectors- Improve durability

ALVAC + gp120/MF59 Licensure RSA

DNA + NYVAC + gp120 Test of Concept Trial NYVAC + gp120

   Basic research

Applied research

Preclinical development Phase I / II Large-scale Efficacy trials

HIV  Vaccine  Pipeline  –  October  2015  

•  epDNA + IL12+ VSV + Single Chain •  DNA + MVA •  DNA + Tiantan-VV

•  Passive Abs •  AAV –bnAb delivery

IAVI-partnered product VxPDC partners

Immunoprophylaxis

•  Adeno 26

Africa  has  very  limited  research  capacity  in  all  fields  of  science-­‐  par@cularly  discovery  science  

Programmmes  such  as    WT  DELTAS,  IAVI  VISTA,  NIH  Fogarty  &  MEPI-­‐  but  more  needed  

New  Minds:  Making  Breakthrough  Discoveries  Nobel  Laureates  1901-­‐2003  in  Three  Disciplines  Stra@fied  by  Age  at  Time  of  Award-­‐

Winning  Discovery  

Dietrich,  Arne,  and  Narayanan  Srinivasan.  2007.  The  op>mum  age  to  start  a  revolu>on.  Journal  of  Crea3ve  Behavior.  41:  54-­‐74.  

•  A  vaccine  will  most  likely  be  needed  to  end  the  HIV/AIDS  epidemic    

 •  The  RV144  vaccine  trial  that  was  par>ally  effec>ve  provides  proof  of  concept  that  an  HIV  vaccine  is  possible  

•  Recent  advances  in  immunogen  design,  delivery  systems  and  basic  understanding  of  HIV  biology  offer  hope  and  a  pathway  to  vaccine  development  

•  Africa  must  invest  in  science  and  especially  in  young  people  for  its  future  

Summary  

Acknowledgements    Useful  discussions  and  slides  •  Frances  Priddy  (IAVI)  •  Simba  Takuva  (HVTN)    •  Dennis  Burton  (Scripps)  •  Dan  H  Barouch  (Harvard)  •  Lynn  Morris  (NICD)  •  Bruce  Walker  (Harvard)    UKZN  •  Ndung’u  lab  (K-­‐RITH)  •  HPP  lab  (UKZN)          

Funding  •  Na>onal  Research  Founda>on  •  CANNSA  network  funded  by  

the  Canadian  CIHR  •  IAVI  •  HHMI  •   Victor  Daitz  Founda>on  •  Bill  and  Melinda  Gates  

Founda>on  •  Wellcome  Trust