Safety and immunogenicity of an oral, replicating adenovirus serotype 4 vector vaccine for H5N1 influenza: a randomised, double-blind, placebo-controlled, phase 1 study

Abstract

SummaryBackgroundReplication-competent virus vector vaccines might have advantages compared with non-replicating vector vaccines. We tested the safety and immunogenicity of an oral adenovirus serotype 4 vector vaccine candidate (Ad4-H5-Vtn) expressing the haemagglutinin from an avian influenza A H5N1 virus.MethodsWe did this phase 1 study at four sites in the USA. We used a computer-generated randomisation list (block size eight, stratified by site) to assign healthy volunteers aged 18–40 years to receive one of five doses of Ad4-H5-Vtn (107 viral particles [VP], 108 VP, 109 VP, 1010 VP, 1011 VP) or placebo (3:1). Vaccine or placebo was given on three occasions, about 56 days apart. Participants, investigators, and study-site personnel were masked to assignment throughout the study. Subsequently, volunteers received a boost dose with 90 μg of an inactivated parenteral H5N1 vaccine. Primary immunogenicity endpoints were seroconversion by haemagglutination-inhibition (HAI), defined as a four-times rise compared with baseline titre, and HAI geometric mean titre (GMT). We solicited symptoms of reactogenicity daily for 7 days after each vaccination and recorded symptoms that persisted beyond 7 days as adverse events. Primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01006798.FindingsWe enrolled 166 participants (125 vaccine; 41 placebo) between Oct 19, 2009, and Sept 9, 2010. HAI responses were low: 13 of 123 vaccinees (11%, 95% CI 6–17) and three of 41 placebo recipients (7%, 2–20) seroconverted. HAI GMT was 6 (95% CI 5–7) for vaccinees, and 5 (5–6) for placebo recipients. However, when inactivated H5N1 vaccine became available, one H5N1 boost was offered to all participants. In this substudy, HAI seroconversion occurred in 19 of 19 participants in the 1011 VP cohort (100%; 95% CI 82–100) and eight of 22 placebo recipients (36%; 17–59); 17 of 19 participants in the 1011 VP cohort (89%; 67–99) achieved seroprotection compared with four of 22 placebo recipients (18%; 5–40); GMT was 135 (89–205) with 1011 VP, compared with 13 (7–21) with placebo. The cumulative frequency of abdominal pain, diarrhoea, and nasal congestion after all three vaccinations was significantly higher in vaccinees than placebo recipients (21 [16·8%] of 125 vs one [2·4%] of 41, p=0·017; 24 [19·2%] of 125 vs two [4·9%] of 41, p=0·027; 41 [32·8%] of 125 vs six [14·6%] of 41, p=0·028; respectively). No serious treatment-related adverse events occurred.InterpretationOral Ad4 vector priming might enhance the efficacy of poorly immunogenic vaccines such as H5N1.FundingWellcome Trust Foundation, PaxVax.

Amplified and Persistent Immune Responses Generated by Single-Cycle Replicating Adenovirus Vaccines

“…In particular, an SC-Ad vaccine should not cause overt adenovirus infections in patients or health care workers. Also, this disabled platform should avoid shedding of active infectious vaccine, as has been observed with RC-Ad vaccines (21).…”

Immune Responses in Macaques to a Prototype Recombinant Adenovirus Live Oral Human Papillomavirus 16 Vaccine

“…The reported abilities of other live rAds to induce humoral immunity have been mixed. An SIV env recombinant elicited SIV-neutralizing antibody transiently after its second administration to macaques (9), but an rAd expressing influenza A virus H5N1 hemagglutinin protein (30) failed to induce antibodies in humans after three immunizations (23). Both of those recombinants primed an antibody response to subsequent immunization with purified protein.…”

“…However, regimens involving a live rAd priming dose and subsequent purified protein boost have proved effective in inducing immune responses to SIV antigens in macaques and to influenza virus antigens in humans (21)(22)(23). To determine whether the Ad5hr-FFIL 16 immunizations had primed a humoral response to HPV16 L1, each macaque was injected at week 35 with 10 g of purified HPV16 VLPs.…”

Development of Vaccines Based on Adenoviral Vectors: A Review of Foreign Clinical Studies (Part 2)

“…В данном исследовании аденовирусная вак-цина использовалась в качестве прайм-вакцины, а в качестве буст-вакцины испытуемые получа-ли субвирионную инактивированную вакцину (Sanofi Pasteur Influenza Virus Vaccine [H5N1]). При этом наблюдалось увеличение титров ан-ти-гемагглютинирующих антител, а также более значительным был Т-клеточный иммунный от-вет на вакцину и уровни IFNg, особенно в груп-пе с наивысшей дозой вакцины (1 × 10 11 вч) [11]. Таким образом, предлагаемая вакцина может быть использована в качестве прайм-вакцины для повышения эффективности существующих слабоиммуногенных вакцин против вируса грип-па.…”