VIRAL IMMUNOLOGY

Measles virus infection diminishes preexistingantibodies that offer protection fromother pathogensMichael J. Mina1,2,3*†, Tomasz Kula1,2, Yumei Leng1, Mamie Li2, Rory D. de Vries4, Mikael Knip5,6,Heli Siljander5,6, Marian Rewers7, David F. Choy8, Mark S. Wilson8, H. Benjamin Larman9,Ashley N. Nelson10‡, Diane E. Griffin10, Rik L. de Swart4, Stephen J. Elledge1,2,11†

Measles virus is directly responsible for more than 100,000 deaths yearly. Epidemiological studies haveassociated measles with increased morbidity and mortality for years after infection, but the reasons whyare poorly understood. Measles virus infects immune cells, causing acute immune suppression. Toidentify and quantify long-term effects of measles on the immune system, we used VirScan, an assaythat tracks antibodies to thousands of pathogen epitopes in blood. We studied 77 unvaccinated childrenbefore and 2 months after natural measles virus infection. Measles caused elimination of 11 to 73% ofthe antibody repertoire across individuals. Recovery of antibodies was detected after natural reexposureto pathogens. Notably, these immune system effects were not observed in infants vaccinated againstMMR (measles, mumps, and rubella), but were confirmed in measles-infected macaques. The reductionin humoral immune memory after measles infection generates potential vulnerability to future infections,underscoring the need for widespread vaccination.

In the time before vaccination, nearly everychild experienced measles, which resultedin millions of deaths. Global measles vac-cination efforts have led to logarithmic re-ductions in the incidence of measles virus

(MV) infections andmeasles-relatedmortality.However,measles remains endemic inmuch oftheworld, affecting >7million people annuallyand causing >100,000 deaths (1–3). After dec-ades of decline, the number of worldwide casesof measles has increased by nearly 300% since2018 as a result of reduced vaccination (2).This increase is likely to be accompanied bysubstantialmortality risks (3). The resurgenceof measles underscores the importance ofunderstanding the full consequences of MVinfection and accurately estimating the valueof measles vaccination (4).Immunosuppression was first documented

when children with measles showed negativecutaneous tuberculin reactions after previouslytesting positive (5). Subsequent studies haveshown decreased interferon signaling, skewedcytokine responses, lymphopenia, and sup-pression of lymphocyte proliferation shortlyafter infection (6). The MV receptor CD150/SLAMF1 (signaling lymphocytic activationmolecule familymember 1) is highly expressedonmemory T, B, and plasma cells, resulting intheir infection and depletion without an effect

on total immunoglobulin G (IgG) levels (7–12).Recovery of the functional immune response,including resolution of lymphopenia, occurs 2to 4 weeks after viral clearance (6, 10, 13, 14).However, MV replication in immune cells hasbeen hypothesized to impair immunememory,potentially causing “immunological amnesia”(10, 15, 16).Most bona fide immune memory cells re-

side in the lymphoid tissues and bone mar-row (17–20). Peripheral blood mononuclearcells are often used for evaluating immuno-logical memory repertoires. However, thesecells are in relative flux owing to recent infec-tions, which limits their utility for measuringlong-term immune memory. Antibodies arethought tobetter represent long-lived humoralmemory (18, 20). Most antibodies in the pe-ripheral blood are produced by bone marrowlong-lived plasma cells (LLPCs) and are im-pervious to disruptions in peripheral memorycells (17–22). Changes in pathogen-specificantibodies measured in the peripheral bloodreflect changes in the long-lived permanentmemory repertoire.Epidemiological evidence has associatedMV

infections with increases in morbidity andmortality for as long as 5 years (15, 23) andsuggests that in the pre-vaccine era, MV mayhave been associated with up to 50% of all

childhood deaths from infectious diseases,mostly from non-MV infections (15). Thisphenomenon might be explained by immuneamnesia. However, to date, no study has suc-cessfully resolved whether measles-inducedimmune amnesia—a reduction in the diver-sity of the immune memory repertoire aftermeasles infections—indeed exists. To addressthis issue, we have studied paired blood sam-ples collected before and after MV infectionusing a seroprofiling tool that allows thedetection of thousands of pathogen-specificantibodies.

Measuring the consequences of measles onimmune memory

During a recent measles outbreak in theNetherlands, families in communities withlow vaccination rates consented to provideblood samples. Plasma was collected beforeand after laboratory-confirmed MV infec-tion from 77 unimmunized children with amean age of 9 (SD ± 2) years, plus five un-immunized childrenwho remained uninfectedduring the study (24). Of the 77 children, 34were reported to havemildmeasles and 43 tohave severe measles [detailed in (24)]. Themean time between sample collections was10 weeks, and mean time of collection afterMV infection was 7 weeks (table S1).To measure the diversity and magnitude of

the epitope-specific antibody repertoires inthese children and controls, we used VirScan(25), a phage-display immunoprecipitationand sequencing (PhIP-Seq) technology (26)developed for virome-wide detection of anti-bodies against viral epitopes. VirScan pri-marily detects antibodies to short contiguousepitopes as opposed to conformational epitopes.The cells producing antibodies to all epitopesare phenotypically similar, aside from theirantibody product. Thus, changes in the anti-body repertoire detected by VirScan representchanges across the spectrum of antibodies, andthese include neutralizing and non-neutralizingantibodies. For this study, we generated anexpanded VirScan library that encodes the fullproteomes of most known human pathogenicviruses (~400 species and strains) plus manybacterial proteins. For each sample, we obtaineda comprehensive measure of the individual’santipathogen antibody repertoire diversity(i.e., the total epitope hits across all path-ogen peptides). We also derived an anti-body epitope binding signal (EBS), which is

RESEARCH

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1Division of Genetics, Brigham and Women’s Hospital, Howard Hughes Medical Institute, Boston, MA 02115, USA. 2Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.3Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA. 4Department of Viroscience, Postgraduate School of Molecular Medicine, Erasmus MC,University Medical Centre Rotterdam, 3015 CN, Rotterdam, Netherlands. 5Children’s Hospital, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland. 6Research Program forClinical and Molecular Metabolism, University of Helsinki, 00014 Helsinki, Finland. 7Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Denver, CO 80045, USA. 8GenentechInc., South San Francisco, CA 94080, USA. 9Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. 10W. Harry Feinstone Department of MolecularMicrobiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. 11Program in Virology, Harvard Medical School, Boston, MA 02115, USA.*Present address: Center for Communicable Disease Dynamics, Department of Epidemiology and Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.†Corresponding author. Email: selledge@genetics.med.harvard.edu (S.J.E.); mmina@hsph.harvard.edu (M.J.M.) ‡Present address: Human Vaccine Institute, Duke University Medical Center, Durham, NC27710, USA.

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a relative measure of antibody titer for eachepitope.We used VirScan to profile the immune

memory antibody repertoires before (time 1)and after (time 2)MV infection. Paired sampleswere also obtained from four control cohorts(n = 119 paired specimens; table S1). Thesesamples were derived from: (i) approximatelyage-matched controls sampled at similar inter-vals (~3months) as themeasles cohorts (controlA; n = 28 paired specimens); (ii) age-matchedcontrols with samples collected ~1 year apart(control B; n = 31); (iii) adult controls withcollection intervals similar to the measles-infected individuals (control C; n = 22); (iv)young children before and after their firstmeasles-mumps-rubella (MMR) vaccination

(MMRvaccinated;n=33); and (v) unvaccinatedchildren from the same community as theMV cases but who remained seronegative forMV (MV negative; n = 5). Control cohorts A,B, and C were individuals with no knownexposure to MV.

Measles modulates the diversity of theantibody repertoire and causes loss ofpreexisting antibodies

We assessed changes in antibody repertoirediversity (measured as the total number ofunique pathogen epitopes recognized, or epi-tope hits) before and after measles relative tothose observed in controls, standardizing thetotal number of epitope hits per individual bycohort for comparison (Fig. 1A). We detected

substantial reductions in the number of path-ogen epitopes recognized after measles butlimited changes in the absence of measles.MV infections were associated with a meanreduction of ~20% in the overall diversity orsize of the antibody repertoire measured byVirScan (Fig. 1B), and this was consistentacross individual pathogens (Fig. 1, D and E,and fig. S1). However, effect sizes varied. No-tably, 12 of the 77 children (16%) lost >40% oftheir overall antibody repertoire diversity. Wedetected increases in MV-specific epitopes inchildren after measles infection or MMR vac-cination (Fig. 1C). No changes in the total IgG,IgA, or IgM levelswere detected, as determinedby quantitative ELISA (enzyme-linked immu-nosorbent assay) (fig. S2). These results suggest

Mina et al., Science 366, 599–606 (2019) 1 November 2019 2 of 8

Fig. 1. Measles virus infectionsreduce antibody diversity.(A) Total epitopes recognized attime 1, left, and time 2, right, percohort. For comparison acrosscohorts, values are standardizedacross all samples per cohort to amean of 0 and standard deviation of1. Each gray line indicates a pairedsample from an individual, and blackconnecting lines indicate meanchange from zero. Boxplots indicateinterquartile range and median.Asterisks indicate paired t testP values. (B) Fold change of totalantibody diversity (i.e., numberof total epitope hits) at time 2 versustime 1. Each point represents onepaired sample from an individual.Boxplots indicate interquartile rangeand median. Asterisks indicatesignificant differences relative tocontrol A (Cntl A), based on stu-dent’s t test P values. (C) Number ofmeasles epitope hits per sample attime 1 and time 2. Thin lines indicatepaired samples. Black lines indicatecohort averages. (D) As in (A), butfor individual viruses. Bonferroni-corrected P values in (A to D): *P <0.05, **P < 0.001, ***P < 0.001,****P < 0.0001. (E) Heatmap indi-cating the change in the totalnumber of epitope hits per speciesbetween time 1 and time 2. Eachcolumn represents an individualpaired sample and each row apathogen. Cohorts are indicated bythe solid bars at top and bottom andare in the same order (left to right)as in (A). Yellow cells indicate thatpathogen was not assayed in thosesamples. Ab, antibody.

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that, rather than a simple loss of total IgG,there is a restructuring of the antibody reper-toire after measles.To measure the full effect of measles on the

pre-measles repertoire and to circumvent inter-ference from new exposures during follow-up,we next restricted analysis to epitopes detectedat the first time point and quantified retentionor loss of epitope recognition. After severe ormild measles, children lost a median of 40%(range: 11 to 62%) or 33% (range: 12 to 73%),respectively, of their total preexisting pathogen-specific antibody repertoires (Fig. 2A and fig.S3). In contrast, controls retained ~90%of theirrepertoires over similar or longer durations.Controlling for interval duration in a bino-

mial random effects model (see materials andmethods),we estimated the per-pathogenprob-ability of antibody retention for each child (Fig.2, B and C). Loss of antibodies after MV in-fection varied widely for specific pathogensand between children. A small fraction of MV-infected individuals retained antibodies sim-ilar to the bottom quartile of the controls.However, the most-affected 20% of childrenlost >50% of the pathogen-specific antibodiesfor most pathogens. In some of these child-ren, up to 70% loss was detected for specificpathogens.Antibody repertoire retention (~90%) was

similar in control cohorts A and B despite thelonger sampling interval in B compared withA (1 year versus 3 months). The retainedantibody repertoire could represent a corestable LLPC repertoire (~90%), and the 10%that was lost could represent a transientrepertoire derived from IgG-secreting B cells

and plasmablasts. This result is consistentwith previous studies that showed no effectof immunosuppressive therapy, such as B cell–depleting anti-CD19 or anti-CD20 treatment,on retention of the majority of the antibodyrepertoire (17, 19, 21, 22). Therefore, measlesis associated with greater loss of antibody-mediated epitope recognition than can beexplained by ablation of B cells, suggesting adirect effect on the LLPC compartment.

Measles decreases the strength ofepitope recognition

Simply counting epitope numbers recognizedbefore and after measles underestimates im-mune memory impairment because epitoperecognition can be detected even when a largefraction of cellular clones producing the rele-vant antibody are eliminated. To quantify therelative abundance of particular antibodies,we generated an EBSmetric, which is a z-scorethat measures the relative enrichment of anepitope in a VirScan immunoprecipitation (seematerials and methods). Thus, EBS representsa VirScan analog of relative antibody titers andcan be measured over time to detect changesin epitope recognition. Significant increasesin EBS for a given epitope usually indicate anew exposure during the follow-up interval.In controls, significant reductions are nor-mally detected when a recent exposure hasoccurred before the first time point, resultingin a peak around time 1 followed by an ex-pected rapid decay of the antibody signal thatis detected at time 2.To evaluate changes in EBS for each path-

ogen species in each child, EBS signals were

clustered by pathogen species and child (EBSPC)and a paired t test (paired per epitope) wasused to test for significant differences attime 2 versus time 1. False discovery rate (fdr)–adjusted P values, sample size, and effect size(calculated as the fold change of the geomet-ric mean at time 2 versus time 1) are shown foreach EBSPC cluster (Fig. 3A and fig. S4).Significant changes in EBSPC were detected

in children in each cohort. Among controls,these changes were distributed equally, belowand above a fold change of 1, indicating recentpathogen exposures before time 1 or duringthe follow-up interval, respectively. Unlike thecontrols, after measles, the significant changesin pathogen-specific EBSPC were both morefrequent and nearly uniformly negative withmedian fold changes (0.58 and 0.62), indicat-ing ~40% reductions in EBSs (Fig. 3A). Theeffect was stronger after severe versus mildMV infections (P < 0.001). We confirmed theseresults by comparing the fold changes in EBSPCto quantitative ELISA assays for adeno-virus, enterovirus, and respiratory syncy-tial virus (RSV) in a selection of childrenwho had decreased or increased EBS, andfound good correlation (correlation coefficientr = 0.73; P < 0.001) (fig. S5, A and B).To further clarify cohort-level changes, we

combined the epitopes from all individualsand evaluated changes on a per-pathogen-species basis across each cohort (fig. S6).Among MV-infected individuals, the medianfold change in EBS measured across all spe-cies was a strongly negative effect (medianfold change: 0.69 or −31%; P < 0.0001). Incontrast, among controls, the antibody EBS

Mina et al., Science 366, 599–606 (2019) 1 November 2019 3 of 8

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Fig. 2. Measles eliminates preexisting immune memory. (A) The proportionof total epitopes detected at time 1 that were retained at time 2. One pointrepresents one child. Bonferroni-adjusted student’s t test P values forsignificant differences relative to control A are shown (****P < 0.0001).(B) Probability of retaining initial antibodies at time 2 for individual pathogensper child. Each point represents a single pathogen per child. Probabilitiesare obtained by fitting a binomial random effects model controlling forinterval duration (materials and methods). Each boxplot represents the

interquartile range and median retention probabilities calculated acrosspathogens for a single child. Points indicate pathogen-specific retentionsthat are outside of the interquartile range per child. Children are rankordered along the x axis by the median (black dot per boxplot) retentionprobabilities. (C) Density distribution of probabilities shown in (B), derived bycollapsing all points in (B) by cohort. Bonferroni-adjusted Wilcoxon signedrank test P values for differences relative to control A are shown(***P < 0.001).

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was significantly changed only for relative-ly few pathogen species, and these wereroughly balanced between positive and nega-tive effects.

Measles disrupts recognition of pathogenepitopes across the cohort

At the cellular level,MVwould not be expectedto preferentially infect particular antibody-secreting cells on the basis of their pathogentargets or the type of antibodies produced(i.e., neutralizing or not). We therefore testedfor cohort-wide differences in EBSs on a per-epitope basis. Across approximately 1100 epi-topes each from the control A and B cohorts,none significantly changed (Fig. 3, B and C,and fig. S7), indicating that antibody epitoperecognition across a group of individuals isremarkably stable, even when changes aredetected at the pathogen species level, as infig. S6. In contrast, EBS was substantiallyreduced in 12% of the 855 epitopes evaluatedaftermildMV infections and in 39%of the 1079epitopes evaluated after severe MV infec-tions (P < 0.0001) (Fig. 3, B and C). Only oneepitope in mild measles and three in severemeasles showed a significant increase, <0.2%overall.VirScandetects neutralizing antibodieswhen

those antibodies target short contiguous epi-topes encoded in the phage display. A well-characterized neutralizing short contiguousepitope is the 24-amino-acid target of the anti-RSVmonoclonal antibody therapiespalivizumaband motavizumab. Among 22 MV-infectedchildren with antibodies against this neutral-izing epitope and without evidence of newRSV exposure, we detected a fold change inEBS of 0.59 (SD ± 0.18; P < 0.001) (fig. S8), inline with the observations above and indicat-ing that the effects ofMV are the same for theneutralizing and non-neutralizing antibodyrepertoires.

The MMR vaccine does not impair theimmune repertoire

Amarked increase in the overall antibody rep-ertoire diversity was noted in MMR-vaccinatedcontrols (Fig. 1), indicating that a similar lossof antibodies does not appear to accompanyreceipt of MMR vaccines compared with MVinfections. However, in infants and young chil-dren, such as the MMR-vaccinated cohort inthis study, the antibody repertoire continuesto add antibody diversity over time (fig. S9).This is particularly true during the secondyear of life, following depletion of maternalantibodies, when measles vaccines are firstgiven. These overall increases in antibody di-versity over time could be obscuring potentialminor impairments from measles vaccine,especially given the relatively long samplinginterval for the vaccinated controls. To deter-mine whether viral responses before or after

MMR vaccination might be impaired, we ana-lyzed EBS for antibodies detected surroundingMMR vaccine. We found no overall change inEBS after MMR vaccination (fig. S10), whichis consistent with observations that the MVvaccine strains are not associated with wide-spread infection of CD150+ lymphocytes (27, 28).

Thus, this higher-resolution analysis failed todetect immune impairment at the epitopelevel. Combinedwith increased epitope diver-sity after MMR vaccination (Fig. 1A), thisanalysis supports decades of observationsthat MMR vaccines do not increase suscep-tibility to subsequent infections (29, 30).

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Fig. 3. Measles virus infections are associated with diminished epitope binding signal. Epitope bindingsignal (EBS) was measured for each epitope. (A) Each point represents one pathogen species per samplepair. Changes in EBS for all epitopes recognized per pathogen per sample pair were compared using aWilcoxon matched-pairs signed rank test. Fdr-adjusted P values (adjusted for a fdr of 5%) are indicatedby color of each symbol. The total number of epitopes included in each paired test (i.e., the numberof epitopes recognized for each species per paired sample) are indicated by the symbol shape. For eachpathogen, the geometric mean (gMean) EBS was calculated at each time and the fold change at time 2versus time 1 was calculated and indicated by the position of each point along the y axis. Density distributionsadjacent to the points reflect the distribution of points that were significantly changed on the basis of afdr P value < 0.05. Only pathogens with antibodies targeting ≥5 epitopes were included. (B) Change in gMeanEBS per epitope, across all paired samples per cohort. Format as in (A), except here each point represents asingle epitope, and the gMean EBS is calculated across all paired samples with the epitope detected. Thecolor of each point represents the fdr-adjusted Wilcoxon matched-pairs signed rank test P value, and shapesindicate the number of paired samples per cohort with antibodies against the particular epitope). Onlyepitopes recognized in >6 paired samples were included. (C) Scatter plot showing each epitope (point) shownin (B), but instead of plotting the fold change, the gMean EBS at time 1 (x axis) versus time 2 (y axis) isplotted. The P values (colors) and samples sizes (shapes) are indicated. MV-specific epitopes were includedand highlighted in green. Epitopes significantly changed in a positive direction are labeled with pathogenspecies name. NS, not significant; PIV-4, parainfluenza virus-4.

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Nevertheless, because of the naturally rapidlyincreasing antibody diversity in this youngcohort at the time ofMMR receipt, we cannotdefinitively rule out the potential for minorreductions of antibody-producing cells withmeasles vaccination.

Reconstruction of the antibody repertoirewith high-transmission pathogens isspatially clustered

Although antibody diversity and abundancewere negatively affected for almost all path-ogens, a subset of children had increased EBSand/or epitope hits for particular pathogensafter measles (Figs. 1, D and E, and 3A; andfigs. S4, S8, and S11), suggestive of potentialrestoration of immune memory after the ini-tial immune depletion.Across all of the pathogen-child combina-

tions with significantly increased EBS aftermeasles, 80% were attributable to only sixpathogens: adenovirus C, influenza A virus,respiratory syncytial virus, human herpesvirus4 (Epstein-Barr virus; HHV-4), Streptococcuspneumoniae and Staphylococcus aureus. Inthese children, the probability of retainingpreexisting antibodies for these pathogenswas relatively high (fig. S12).If reconstruction of the antibody repertoire

requires new exposures, children experiencingrepertoire reconstruction for transmissiblepathogens should cluster spatially. Using postal

codes and household identifiers, we observedclustering of pathogen-specific repertoire re-construction at both the postal code or schoollevel and the household level (Fig. 4). Among19 children with increased adenovirus C anti-body EBS, eight (42%) came from a singlepostal code (number 7) that included only12 (16%) of the 77measles cases (Fig. 4A). Thus,children in this postal code had significantlyincreased odds [odds ratio (OR) 9.4; Fisher’sexact test, P < 0.001] of recovering their ade-novirus C repertoire versus other postal codes,suggesting recovery is associated with patho-gen transmission. Moreover, six of these chil-dren (75%) shared a household with anotherchild with increased adenovirus C EBS. Wefound similar clustering effects for other res-piratory pathogens: influenza A virus [of eightchildren with increased influenza A EBS,five (63%) were from a single postal code rep-resenting only 26% of the measles cases (OR5.8; P < 0.05) and two were from the samehousehold; Fig. 4B]; RSV [of nine with in-creased EBS, five (56%) were from the samepostal code (OR4.5;P<0.05) and four of them(44%) shared a house; Fig. 4C]; rhinovirus [of12 with increased EBS, eight (67%) shared ahousehold with at least one other child withincreased rhinovirus EBS]; and S. pneumoniae[of 13, seven (54%) came from a single postalcode (OR 4.5; P < 0.05) and two shared ahousehold]. Combined, these indicate local

pathogen transmission and suggest that re-construction of the antibody repertoire occurson a per-pathogen basis and is associated withnew exposures.In contrast to the highly transmissible respi-

ratory pathogens above, where mean EBS wasincreased after measles infection, we foundthat for chronic viruses [i.e., HHV-4 and hu-manherpesvirus 5 (cytomegalovirus; HHV-5)],there was no evidence of spatial clustering.Further, only 6 out of 12 individuals (50%)withincreased HHV-4 antibody EBS also devel-oped antibodies against newHHV-4 epitopes.HHV-5 behaved similarly, with only 33% ofindividuals with increased HHV-5 antibodyEBS also developing new antibodies to pre-viously untargeted HHV-5 epitopes. The lackof development of antibodies targeting newepitopes, despite increases in EBS of existingantibodies for these two pathogens, is dif-ferent from what we observed for the more-transmissible viruses noted above, in which90% of pathogen-specific increases in EBS attime 2 were associated with development ofnew antibodies against previously unrecog-nized pathogen-specific epitopes. An increasein EBS without addition of new epitope rec-ognition points toward reinfection with orreactivation of the same virus.Two additional notable pathogens for which

positive changes in EBS were often detectedafter measles were the bacteria S. pneumoniae

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A B C

Fig. 4. Increases in antibody epitope binding signal cluster within householdsand in postal units. We tested whether individuals with increased EBS indicatenew exposures due to pathogen transmission by looking for evidence of spatialclustering among children with increases in EBS. In (A to C), each child (node) isconnected by an edge to their postal code (indicated by a central node with anassigned value, 2 through 7). Children shown as single nodes were the only children

studied from their postal code. Children from the same household are connected byan edge and encircled by dashed gray ovals. Each of the three viruses whereincreases in EBS were most common are shown: (A) adenovirus C, (B) influenza Avirus, and (C) respiratory syncytial virus. Children with significantly increased EBSfor the pathogen (indicating exposure during the interval) are highlighted with redcircles and those with decreased or unchanged EBS with gray circles.

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and S. aureus. Acute viral respiratory infections,including measles, increase susceptibility torespiratory bacterial infections (6, 31–33).After measles, new acquisitions of bacteriaor increased replication of already colonizingbacteria could elicit antibody responses andreinstate antibody diversity and protectionagainst these pathogens. In line with this, weobserved net increases in antibody diversity,including development of antibodies againstnew epitopes, and increases in EBS for S. aureus[the only pathogen for which a net positivechange in antibody diversity or EBS was de-tected after measles; 45 of 77 children (58%)had increased EBS] (Fig. 1 and fig. S11). In-creases were also observed for S. pneumoniae,although theoverall cohort-level effect remainednegative.

Reconstruction of the antibody repertoirethrough reexposure after measles carries risks

Despite the potential benefits of reinstatingthe antibody repertoire, exposure to pathogensaftermeasles—especially when in the presenceof diminished preexisting immunememory—

can carry risks. Ten of 43 children (23%) withseveremeasleswere diagnosedwith acute otitismedia (AOM;most commonly pneumococcal),whichwas associatedwith a threefold increasein odds of carrying greater pneumococcal anti-body diversity after measles compared withchildren without an AOM diagnosis. In addi-tion, two childrenwithmildmeasles andAOMand one with a diagnosis of bacterial pneumo-nia had increased pneumococcal antibody di-versity at follow-up. Combined, these effectssuggest that the antibody repertoire beginsrebuilding soon after measles, through path-ogen exposures, and that pathogen exposureafter measles, while serving to reinstate im-mune memory, may pose excess risk.

Experimental MV infection confirms adecrease in previously acquiredimmune memory

To confirm the findings above using a con-trolled experimental setting with longer follow-up, we used VirScan to profile the antibodyrepertoire in plasma collected before and5 months after experimental MV infection of

four rhesus macaques (34). The overall diver-sity of the antibody repertoire was decreasedan average of 26% (range: 21 to 35%), andreductions were distributed across pathogens(Fig. 5A). Notable exceptions were observedfor simian foamy virus and Epstein-Barr virus,both of which can reactivate during immunedysregulation and thus may be early con-tributors to repertoire reconstruction. Asexpected, we detected increases in recogni-tion of MV epitopes (Fig. 5B). Out of 21 MVepitopes recognized after measles, only one(phosphoprotein/V protein 29) was recognizedbefore infection and was reduced by 40%. Thislikely represented a cross-reactive epitope thatwas diminished along with the rest of therepertoire.Eachmonkey lost, on average, 40 to 60% of

its preexisting antibody repertoire (Fig. 5C),and this loss persisted for at least 5 monthsafter MV infection. In each monkey, the frac-tions lost were distributed across the path-ogens, which is expected for a virus thatindiscriminately infects antibody-secretingcells.

Mina et al., Science 366, 599–606 (2019) 1 November 2019 6 of 8

Fig. 5. Measles virus infection inmacaques deletes preexistingimmune memory. Four rhesusmacaques (14Y, 31Y, 46Y, and 50Y)were infected with the Bilthovenstrain of wild-type MV [detailed in(34)], and plasma samples werecollected before and 5.1 months afterinfection. (A) Heatmap showingthe percentage change in totalepitopes recognized per pathogenin each monkey from time 1 totime 2. Pathogens with >10 uniqueepitopes recognized at either timepoint per macaque are shown.The color and text indicate percentchange in total epitopes recognizedper pathogen species beforeversus after infection. (B) Heatmapshowing the signal strength ofanti-measles antibodies (EBS) foreach epitope for which at leastone monkey developed an antibody.Colors and text of each cell representthe respective EBS values.Lettersindicate the MV protein (F, fusionprotein; H, hemagglutinin; N, nucleo-protein; and P, phosphoprotein),and the numbers indicate theposition along the protein of the firstamino acid of the 56-amino-acidpeptide. (C) The fractions of epitopesrecognized before MV infectionthat remained 5 months after areshown (0 months after infection isbaseline and thus set to 1 for all pathogens). Each gray line indicates a different pathogen, and the dark black line indicates the average across the pathogens. Theboxplot summarizes the interquartile range and median fraction retained across the pathogens.

Moll. contag . virusRSV

NorovirusCoronavirus HKU1

Herpesvirus 6BEpstein Barr virus

Rhinovirus BHerpes zoster

Betapapillomavirus 1Macaque SFV

Simian virus 40Adenovirus AAdenovirus FAdenovirus B

Influenza B virusS. pneumoniae

Enterovirus ASaimiriine herpesvirus

Helicobacter pyloriAdenovirus CHerpesvirus 7

Herpesvirus 6ACytomegalovirus

Adenovirus DRotavirus A

Tanapox virusS. aureus

Vaccinia virusRhinovirus A

AlphapapillomavirusEnterovirus BEnterovirus C

Influenza A virus

-

A B

C

P_449P_421P_393P_253P_225P_141P_113

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1.00

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21%

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Cumulative evidence supports theestablishment of an immune amnesia stateafter measlesUsing VirScan, we quantified the effects ofmeasles on antipathogen antibody repertoiresin plasma obtained before and after naturaland experimental MV infections. We foundthat measles is associated with large reduc-tions in both the diversity of the antibody rep-ertoire and magnitude of the binding signal,likely reflecting reduced antibody titers result-ing from diminished numbers of cells produc-ing the respective antibody. The reduction ofdiversity may be greater than we report be-cause even if particular antibody-producingcells have been eliminated, an antibody half-life of ~3 weeks (35) means that residual anti-bodies were still detectable at the time ofsampling. Our findings show that after recov-ery from MV infections, individuals enter astate in which immune functionality is re-stored, but memory cell elimination inducedby measles may alter previously acquiredmemory.MV can infect 20 to 70% of memory cells,

including B cells, T cells, and plasma cells inthe lymphoid tissue and peripheral bloodduring the first 3 to 10 days after infection(7, 10, 24). Clinical trials of systemic adminis-tration of engineeredMV for oncolytic therapyof multiple myeloma also demonstrated effi-cient entry of MV into the bone marrow andplasma cell infection (36). In wild-type MVinfections, lymphocytes undergo rapid prolif-eration during immune activation (37), andlymphocyte counts (and other immunologicalmarkers) return to normal levels within weeksof infection. Thus, the immunological toll ofmeasles is often considered limited to thatperiod. After experimental MV infection inmonkeys, we found that we could no longerdetect up to 60% of the antibody repertoire,and this persisted for at least 5 months. Thisloss could be permanent, owing to elimina-tion of B cells as well as LLPCs (11), althoughwe cannot rule out possible involvement ofadditional unknown pleiotropic effects thatmay also cause antibody-secreting cells todown-regulate antibody production. Further-more, because T cells also express SLAM andare infected by MV, T cell immunity may bediminished through similar mechanisms, andthis could explain the loss of cutaneous tu-berculin reactions after measles (5). Lastingremissions of autoimmune-related disordersaftermeasles have beendetected by researcherssince the 1940s (38), supporting the potentialpersistence of immune suppression and point-ing to persistent long-term effects. BecauseLLPCs are terminally differentiated and donot replicate (39), the rebuilding of immunememory after measles-induced LLPC elimina-tion would likely require reexposures, eitherthrough natural infection or vaccination; thus

it could potentially take months or years toreturn the immune repertoire back to baselinefor all relevant pathogens. During the rebuild-ing process, individuals would potentially beat increased risk for other infectious diseases.Revaccination with routine childhood vac-cines after measles could help to mitigatelong-term suffering that might stem fromimmune amnesia and subsequent increasedsusceptibility to other infections.We previously reported evidence that mea-

sles epidemics link to population mortality 2to 3 years later (15, 40). We hypothesized thatthe observed dynamics could potentially beexplained by an immunomodulatory effect ofmeasles, similar to what we show here. Wefound no such debilitative effects for the liveMMR vaccine (15). Furthermore, because, inthe prevaccine era, MV infected nearly allchildren within the first decade of life, thevaccinemay have contributed to considerablygreater benefits by preventing measles andimmune amnesia. By preserving immunity,measles vaccines may have reset overall base-line morbidity and mortality rates to lowerlevels (15).Given the variation in the degree of immune

repertoire modulation we observed, we antic-ipate that future risk of morbidity and mortal-ity after measles would not be homogeneousbut would be skewed toward individuals withthe most severe elimination of immunologicalmemory. These findings underscore the cru-cial need for continued widespread vaccina-tion. More than 7million people are estimatedto have been infected with measles in 2018(1–3). Comprehensive coverage with MV vac-cine would not only help prevent the >120,000deaths that will be directly attributed tomeasles this year, but, by preventing MV im-mune amnesia and thus preserving immu-nity, MV vaccines could also avert potentiallyhundreds of thousands of additional deathsattributable to the lasting damage to the im-mune system. The WHO recently reportedthat between 2000 and 2017,MV vaccines havepreventedmore than 21million deaths directlyattributable to measles (41). These findingssuggest that the number of deaths avertedmight be much greater, and they attest to theimmense public health value of the measlesvaccine.

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9. B. Hahm, N. Arbour, M. B. Oldstone, Virology 323, 292–302 (2004).10. R. D. de Vries et al., PLOS Pathog. 8, e1002885 (2012).11. J. De Salort, J. Sintes, L. Llinàs, J. Matesanz-Isabel, P. Engel,

Immunol. Lett. 134, 129–136 (2011).12. B. M. Laksono et al., J. Virol. 92, e00131-18 (2018).13. J. J. Ryon, W. J. Moss, M. Monze, D. E. Griffin, Clin. Diagn. Lab.

Immunol. 9, 994–1003 (2002).14. V. G. Tamashiro, H. H. Perez, D. E. Griffin, Pediatr. Infect. Dis. J.

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11 (2017).30. W. J. Moss, D. E. Griffin, Nat. Rev. Microbiol. 4, 900–908

(2006).31. M. J. Mina, J. A. McCullers, K. P. Klugman, mBio 5, e01040-13

(2014).32. M. J. Mina, K. P. Klugman, Lancet Respir. Med. 2, 750–763 (2014).33. R. Cole, J. Am. Med. Assoc. 70, 1147–1153 (1918).34. A. N. Nelson et al., Sci. Rep. 7, 11474 (2017).35. P. R. Hinton et al., J. Immunol. 176, 346–356 (2006).36. A. Dispenzieri et al., Leukemia 31, 2791–2798 (2017).37. D. E. Griffin, B. J. Ward, E. Jauregui, R. T. Johnson, A. Vaisberg,

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ACKNOWLEDGMENTS

We express our gratitude to the participants, including children,parents, school staff, and other volunteers, who provided timeand samples for this work. We also thank B. T. Grenfell andC. J. E. Metcalf for their early insights into this work andE. Shrock for assistance with assays. Funding: This work wassupported by a grant from the Value of Vaccine ResearchNetwork to S.J.E. and M.J.M.; a grant from the Gates Foundationto S.J.E.; an NIH/NIAID U24 grant to H.B.L. and S.J.E.; a grantfrom the European Union Seventh Framework Program(grant 202063) and a grant from the Academy of Finland(Centre of Excellence in Molecular Systems Immunology andPhysiology; grant 250114) to M.K.; NIH R01 DK032493 to M.R.;NIH R21 AI095981 and R01 AI131228 to D.E.G.; and a grantfrom PREPARE Europe (EU FP7 grant 602525) to R.L.d.S. S.J.E.is an Investigator with the Howard Hughes Medical Institute.Author contributions: Conceptualization: M.J.M., T.K., R.L.d.S.,and S.J.E.; Investigation: M.J.M., T.K., Y.L., and M.L.; Reagentsand samples: H.S., M.K., D.F.C., M.R., M.S.W., D.E.G., A.N.N.,H.B.L., R.D.d.V., and R.L.d.S.; Writing: M.J.M., T.K., and S.J.E.;Supervision: S.J.E. Competing interests: M.S.W. and D.F.C.are employees of Genentech. S.J.E. is a founder of TSCANTherapeutics, MAZE Therapeutics, and Mirimus. S.J.E. serveson the scientific advisory boards of CRISPR Therapeutics,Homology Medicines, TSCAN Therapeutics, and XChem and is

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an adviser for MPM Capital, none of which affect this work.M.J.M. has served as a member of Sanofi advisory board for RSVtherapeutics. D.E.G. is a member of the GlaxoSmithKlineVaccine Research and Development Advisory Board. S.J.E., T.K.,and H.B.L. are inventors on a patent application filed by TheBrigham and Women's Hospital (US20160320406A) that coversthe use of the VirScan library to identify pathogen antibodiesin blood. All other authors declare no competing interests. Data

and materials availability: The VirScan library is availableunder a material transfer agreement. Data are available in themain text, the supplementary materials, or on Dryad (42).

SUPPLEMENTARY MATERIALS

science.sciencemag.org/content/366/6465/599/suppl/DC1Materials and Methods

Figs. S1 to S12

Table S1

References (43–45)

View/request a protocol for this paper from Bio-protocol.

9 July 2019; accepted 30 September 201910.1126/science.aay6485

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pathogensMeasles virus infection diminishes preexisting antibodies that offer protection from other

Choy, Mark S. Wilson, H. Benjamin Larman, Ashley N. Nelson, Diane E. Griffin, Rik L. de Swart and Stephen J. ElledgeMichael J. Mina, Tomasz Kula, Yumei Leng, Mamie Li, Rory D. de Vries, Mikael Knip, Heli Siljander, Marian Rewers, David F.

DOI: 10.1126/science.aay6485 (6465), 599-606.366Science 

, this issue p. 599Scienceother pathogens. These adverse effects on the immune system were not seen in vaccinated children.infection can greatly diminish previously acquired immune memory, potentially leaving individuals at risk for infection bynatural infection with measles virus as well as in children before and after measles vaccination. They found that measles

comprehensively analyzed the antibody repertoire in children before and afteret al.a blood test called VirScan, Mina unclear. This question has become increasingly important given the resurgence in measles epidemics worldwide. Usingfunctionally impairs immune cells. Whether measles infection causes long-term damage to immune memory has been

Many of the deaths attributable to measles virus are caused by secondary infections because the virus infects andThe toll of measles on the immune system

ARTICLE TOOLS http://science.sciencemag.org/content/366/6465/599

MATERIALSSUPPLEMENTARY http://science.sciencemag.org/content/suppl/2019/10/30/366.6465.599.DC1

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