Prevalence of serum neutralizing antibodies against chimpanzee adenovirus 63 and human adenovirus 5 in Kenyan Children, in the context of vaccine vector efficacy

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<ul><li><p>Vaccine 27 (2009) 35013504</p><p>Contents lists available at ScienceDirect</p><p>Vaccine</p><p>com</p><p>Letter to t</p><p>Prevalence us 63context of</p><p>a r t i c l</p><p>Keywords:Simian adenovMalaria vaccinVector neutral</p><p>arumildrenusefuction.f then wh</p><p>ant chasurefromn (agtibods signt AdC</p><p>1. Introduc</p><p>Plasmodlion people annually [1], one million children die from P. falciparummalaria every year [2]. A vaccine against malaria could reduce theburden of disease, alongside other strategies.</p><p>Cellular immunity induced by a vaccine could protect againstthe pre-erythrocytic stages of Plasmodium infection. Irradiated P.falciparumtect agains[3]. In micis dependebe compleby adoptiv(TRAP)-specinesencodof sporozo</p><p>Adenovgenic delivvaccines hcyte responagainst inf</p><p>The efcell immun[12,13], is lvector serothe transgeas well asantibodiesvector can</p><p>USAies [1pid</p><p>oodresponses to an AdHu5 vector-based HIV-1 vaccine were sig-nicantly lower in human volunteers showing serum antibodyimmunity to AdHu5 [25].</p><p>Previous studies suggest that theprevalenceofneutralizinganti-</p><p>0264-410X/$doi:10.1016/j.sporozoites administered to human volunteers can pro-tmalaria following experimental challenge for 6monthse, the immunity generated by irradiated sporozoitesnt on CD8+T cell activity: non-immunized mice cantely protected from infection with P. yoelii sporozoitese transfer of thrombospondin related adhesion proteincic CD8+T lymphocytes [4]. In humans poxvirus vac-ingME-TRAPhave reducedparasiteburdens in the livers</p><p>ite challenged vaccinees by around 90% [5].irus recombinant vectors could be safe and immuno-ery vehicles for a malaria vaccine. Adenovirus-basedave been shown to induce a strong cytolytic T lympho-se to the transgenic antigen, and can protect completely</p><p>ection in a mouse model [6].cacy of adenovirus-based vaccines at generating CD8+Tity to a transgene [711], and protecting from infectionower in subjects with existing humoral immunity to thetype. Neutralizing antibodies decrease the expression ofne carried by the vector [7], and may be responsible for,predictive of, decreased immunogenicity. Neutralizingto Human Adenovirus 5 (AdHu5), a common vaccine</p><p>didate, have an adult prevalence between 30% and 50%</p><p>bodies to chimpanzee adenoviruses may be very low in targetpopulations [1721]. Chimpanzee adenovirus vectors, like humanadenovirus vectors, can generate CD8+T cell immunity to trans-genic peptides [19]. Chimpanzee adenovirus 63 (AdC63) has beenused to create a replication-decient, ME-TRAP transgenic P. falci-parum malaria vaccine, currently in Phase I clinical testing as therst simian virus to be assessed as a vaccine vector in humans.</p><p>The object of this study was to quantify the prevalence ofneutralizing antibodies to AdHu5 and AdC63 in a population ofchildren likely to benet from a malaria vaccine. Children are at thegreatest risk from P. falciparum malaria; the sample was of childrenaged from 1 to 6 years from Kili, Kenya. The virus neutralizationtiters in this group would be informative as to the clinical scopeof a vaccine based on the AdC63 vector. Here we report levels ofneutralizing antibodies against AdC63 in a target population formalaria vaccination.</p><p>2. Materials and methods</p><p>2.1. Viruses</p><p>Replication-decient adenovirus transgenic E1-decient vec-tors expressing secreted alkaline phosphatase (SEAP), AdHu5SEAP</p><p> see front matter 2009 Elsevier Ltd. All rights reserved.vaccine.2009.03.080journa l homepage: www.e lsev ier .</p><p>he Editor</p><p>of serum neutralizing antibodies against chimpanzee adenovirvaccine vector efcacy</p><p>e i n f o</p><p>iral vectoreizing antibodies</p><p>a b s t r a c t</p><p>Vaccination against Plasmodium falcipand decrease its high mortality in chrying P. falciparum epitopes may bepre-erythrocytic stage of malaria infein antibody-mediated neutralization owas to examine a population of childrenity to replication-decient recombinadenovirus 5 vector (AdHu5). We mesera, taken from a cohort of childrenassay.We found that 23% of the childreand 4% had high-titer neutralizing anLow-level neutralization of AdC63 waneutralization level. We conclude thavaccine in children.</p><p>tion</p><p>ium falciparum causes clinical malaria in up to 650 mil-</p><p>in thecountrto a rachildh/ locate /vacc ine</p><p>and human adenovirus 5 in Kenyan Children, in the</p><p>malaria could reduce the worldwide burden of this disease,. Replication-defective recombinant adenovirus vectors car-l as part of a vaccine that raises cellular immunity to theHowever, existing immunity to the adenovirus vector resultsvaccine vector, and reduced vaccine immunogenicity. Our aimo are at risk from P. falciparum malaria for neutralizing immu-impanzee adenovirus 63 vector (AdC63), compared to humand 50% and 90% vector neutralization titers in 200 individualKenya, using a secreted alkaline phosphatase neutralizationed 16 years) had high-titer neutralizing antibodies to AdHu5,ies to AdC63. Immunity to both vectors was age-dependent.icantly less frequent than AdHu5 neutralization at the 90%63 may be a useful vector as part of a prime-boost malaria</p><p> 2009 Elsevier Ltd. All rights reserved.</p><p>and Western Europe, and up to 98% in surveyed African417]. Normal exposure to human adenoviruses leadsincrease in neutralizing antibody prevalence during[18]. In the recent STEP Study CD8+T lymphocyte</p></li><li><p>3502 Letter to the Editor / Vaccine 27 (2009) 35013504</p><p>and AdC63SEAP, were obtained from Okairs, Italy. The transgenicviruses share penton, hexon and bre coding regions with vaccinevectors and wild-type viruses of the same serotype.</p><p>The ratio of virus particles per cell used in the neutralizationassay was cintensity w</p><p>2.2. Human</p><p>Two hunfor pre-vacchealthy chiKili, Easteparticipants</p><p>EthicalResearch Coshire Resea</p><p>Sera weprior to use</p><p>2.3. Virus n</p><p>Adenoviassessed us[21].</p><p>HEK293Recombinations of serdilutions wple was tesand human</p><p>Supernausing CSPDLuminescen1450 luminwas standatration wasconcentrati</p><p>NeutraliSEAP conce90% neutrawas calcula</p><p>2.4. Statisti</p><p>To evalugroups of chtiters was a95% condefor binomiagroups, allo</p><p>3. Results</p><p>We rstagainst AdHchildren agJunju sub-losequently pvaccine [22</p><p>Of the 2were foundantibody (i.against thetralizing anAdHu5 vect</p><p>eutra6 year</p><p>NAbe, titort</p><p>8.0)w7.6). In contrast to the ndings for high titer antibodies, lowtibodies at the 50% neutralization level were not found to</p><p>re common against AdHu5 than for AdC63 (14% vs 17.5%;).neutralization titres were also tested. There was a sig-</p><p>t difference between the incidence of high neutralizationgainst AdHu5 (12.5%; 7.319.5%) and AdC63 (one child; 0.8%;) in the 36 years age group. No children had any detectabledy neutralization at this level against AdC63 in the 12 yearsoup (condence interval 04.0%); seven (9.7%; 4.019.0%)n in the same age group had detectable antibodies against. Thedifference inhighneutralization titer incidencewasnotant in this age group. Low antibody titers at the 90% neutral-level were found to be signicantly higher against AdHu5</p><p>gainst AdC63 (15% vs 2%; p</p></li><li><p>Letter to the Editor / Vaccine 27 (2009) 35013504 3503</p><p>children aged 12 years had high neutralization titers to AdHu5(i.e. &gt;200), compared to 12.8% in the South African cohort of thesame age. The subsequent age groups (36 years in this Kenyansample and 27 years in the South African cohort) had 31.3% preva-lence and 38.5% prevalence of high AdHu5 neutralization titers,respectively</p><p>We obseization agaitested, andaged 36 yeto human alation. Thegroups, if reareas, couldbasedvacciwith peak isen. High-tican reduceof 100 timethe presencneutralizingthere is wigous adenoimmunogenlowing hethave not ointerferenceimmunogen</p><p>Low neution level tetiters, whic90% neutraneutralizatiilar to thoslevel, in simtralization(2.0%; 0.55</p><p>Neutraliother serumhumans haies of otherserum neutUSA, neutra68 in healthigh neutra6 and 1werCote dIvoir[1], the aduadenovirusepartially neagainst ano</p><p>The resumalaria-endthe exposurprovide newhumans. ThAdC63 in bofor its poten</p><p>Acknowled</p><p>This woWellcome Ppermission(KEMRI).</p><p>References</p><p>[1] Snow RW, Guerra CA, Noor AM, Myint HY, Hay SI. The global distribution ofclinical episodes of Plasmodium falciparum malaria. Nature 2005;434:2147.</p><p>[2] Rowe AK, Rowe SY, Snow RW, Korenromp EL, Schellennerg JR, Stein C, et al.The burd</p><p>demiode DFinst Fp Medsmithyoeli</p><p>rozoitbsteranced</p><p>ng theS USA</p><p>ng ZQirus r6;219imiroativeciniaan im</p><p>anzarfety a</p><p>edeliv2006geraldimian</p><p>unolsis N,immuctionarnerl. Immcine r6;80:ingermpan6;346es-SaSingletors aink P,ative snovirone Sirus ti-ad5hesusina SFectiveckertl. Gen</p><p>humunog</p><p>rner AendenSub</p><p>S, Zhn ade6;87:teredety of ae-Amal. Qualinein th</p><p>304on P, Ofollow-TRAPng ZQzee ad6;12:on P, Mof theodinglaria eElrathaccinelysis.rmuleponse9;6:1.rved a very low prevalence of high-titer serum neutral-nst AdC63 when compared to AdHu5 in all 200 childrenthis difference was particularly marked among childrenars. This probably reects the acquisition of immunitydenoviruses with age, as they circulate in the popu-low prevalence of AdC63 neutralization in both agepresentative of other populations in malaria endemicindicate greater exibility in the use of an AdC63-</p><p>ne in childrenof different ages, soprime-boost regimensmmunogenicity and antimalarial efcacy could be cho-ter serum neutralization is clinically signicant, as thisthe effective number of vaccine carriers by the orders [7]. CD8+T cell vaccine responses are decreased ine of vector-reactive CD8+T cells, which correlate withantibodies in humans [2426]. It is unclear whether</p><p>despread CD8+T cell interference between heterolo-virus vectors; studies of CD8+T cell adenovirus vaccineicity have shown marginally decreased responses fol-erologous vector immunization [7,9] though othersbserved this effect [14,15]. Heterologous CD8+T cell</p><p>appears to have little impact on adenovirus vectoricity.tralization titers observed depended on the neutraliza-sted; In this study, we considered 50% neutralizationh are more sensitive to low-level neutralization, andlization titers, which are more specic. Low AdHu5on titres at the 90% level (15.0%; 10.420.7%) are sim-e observed by Thorner et al. at the 90% neutralization</p><p>ilar age groups (15.4%) [19]. AdC63 low-titer neu-was signicantly lower across the two age groups5.0%).zation of AdC63 could result from cross-reactivity of</p><p>antibodies to this vector. Circulation of AdC63 ins not been documented, but cannot be ruled out. Stud-chimpanzee adenoviruses yielded very low levels ofralization in other populations tested [1721]. In thelizing antibody titers against Chimpanzee Adenovirushy volunteers were measured at 2% [17]; in Thailand,lization titers against chimpanzee adenovirus serotypese 1% and 2%, respectively [20]. In Cameroon, Nigeria ande, all countries with a holoendemic malaria incidencelt prevalence of antibodies against two chimpanzees did not exceed 10% [23]. It is possible that AdC63 isutralized by antibodies against other adenoviruses, orther pathogen.lts of this study in a small cohort of children from aemic area conrm the ndings of previous studies one and serum neutralization of AdHu5 in children, andndings about chimpanzee adenovirus immunity in</p><p>e low prevalence of high titer neutralizing antibodies toth target age groups in our cohort is very encouragingtial use as a malaria vaccine vector.</p><p>gements</p><p>rk was supported by the Wellcome Trust. AVSH is arincipal Research Fellow. 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