Assessment of the Safety and Immunogenicity of 2 Novel Vaccine Platforms for HIV-1 Prevention: A Randomized Trial

Abstract

Background: A prophylactic HIV-1 vaccine is a global health priority.

Objective: To assess a novel vaccine platform as a prophylactic HIV-1 regimen.

Design: Randomized, double-blind, placebo-controlled trial. Both participants and study personnel were blinded to treatment allocation. (ClinicalTrials.gov: NCT01215149).

Setting: United States, East Africa, and South Africa.

Patients: Healthy adults without HIV infection.

Intervention: 2 HIV-1 vaccines (adenovirus serotype 26 with an HIV-1 envelope A insert [Ad26.EnvA] and adenovirus serotype 35 with an HIV-1 envelope A insert [Ad35.Env], both administered at a dose of 5 × 1010 viral particles) in homologous and heterologous combinations.

Measurements: Safety and immunogenicity and the effect of baseline vector immunity.

Results: 217 participants received at least 1 vaccination, and 210 (>96%) completed follow-up. No vaccine-associated serious adverse events occurred. All regimens were generally well-tolerated. All regimens elicited humoral and cellular immune responses in nearly all participants. Preexisting Ad26- or Ad35-neutralizing antibody titers had no effect on vaccine safety and little effect on immunogenicity. In both homologous and heterologous regimens, the second vaccination significantly increased EnvA antibody titers (approximately 20-fold from the median enzyme-linked immunosorbent assay titers of 30-300 to 3000). The heterologous regimen of Ad26-Ad35 elicited significantly higher EnvA antibody titers than Ad35-Ad26. T-cell responses were modest and lower in East Africa than in South Africa and the United States.

Limitations: Because the 2 envelope inserts were not identical, the boosting responses were complex to interpret. Durability of the immune responses elicited beyond 1 year is unknown.

Conclusion: Both vaccines elicited significant immune responses in all populations. Baseline vector immunity did not significantly affect responses. Second vaccinations in all regimens significantly boosted EnvA antibody titers, although vaccine order in the heterologous regimen had a modest effect on the immune response.

Primary funding source: International AIDS Vaccine Initiative, National Institutes of Health, Ragon Institute, Crucell Holland.

Figure 1. Maximum local and systemic reactions

Data from all first vaccinations were pooled based on vaccine received and then respective homologous and heterologous regimens were examined. The Y-axis represents the percentage of volunteers experiencing reactogenicity events and the X-axis the study group(s). Panel A for local reactions and panel B for systemic reactions through Day 7 after each vaccination by study group all sites combined and by region. Volunteers self-assessed reactogenicity with a memory aid on Day 0 (evening of vaccine/placebo administration) and daily through Day 7. Safety data for placebos by study group for all sites combined and by region is shown in the far right column of each quadrant. The figure shows the maximum severity assessment grade recorded. The severity grade of the reactogenicity events is indicated by color codes (none: white; mild: yellow; moderate: orange; severe: red).

Figure 1. Maximum local and systemic reactions

Data from all first vaccinations were pooled based on vaccine received and then respective homologous and heterologous regimens were examined. The Y-axis represents the percentage of volunteers experiencing reactogenicity events and the X-axis the study group(s). Panel A for local reactions and panel B for systemic reactions through Day 7 after each vaccination by study group all sites combined and by region. Volunteers self-assessed reactogenicity with a memory aid on Day 0 (evening of vaccine/placebo administration) and daily through Day 7. Safety data for placebos by study group for all sites combined and by region is shown in the far right column of each quadrant. The figure shows the maximum severity assessment grade recorded. The severity grade of the reactogenicity events is indicated by color codes (none: white; mild: yellow; moderate: orange; severe: red).

Figure 2. Distribution of ELISA titers 4 weeks after each vaccination per regimen

A) RW020 ELISA Titers (RW020 Env is homologous to the Ad26 Env insert); B) UG37 ELISA Titers (UG37 Env is 81.2% homologous to the Ad35 Env insert). Second vaccinations were at month 6 in Groups A and B, and month 3 otherwise. Boxes represent the 1^st and 3^rd quartiles (IQR). Red lines indicate median titer. Whiskers extend to the 5^th and 95^th percentiles. White/orange boxes represent negative/positive baseline Ad26 NAb (A) and Ad35 NAb (B) values. On the X-axis, B, 1 & 2 represent baseline and 4 weeks post first and second vaccinations respectively.

Figure 2. Distribution of ELISA titers 4 weeks after each vaccination per regimen

A) RW020 ELISA Titers (RW020 Env is homologous to the Ad26 Env insert); B) UG37 ELISA Titers (UG37 Env is 81.2% homologous to the Ad35 Env insert). Second vaccinations were at month 6 in Groups A and B, and month 3 otherwise. Boxes represent the 1^st and 3^rd quartiles (IQR). Red lines indicate median titer. Whiskers extend to the 5^th and 95^th percentiles. White/orange boxes represent negative/positive baseline Ad26 NAb (A) and Ad35 NAb (B) values. On the X-axis, B, 1 & 2 represent baseline and 4 weeks post first and second vaccinations respectively.

Figure 3. Distribution of ELISA titers 4 weeks after the second vaccination at month three in heterologous administration groups

The two left boxes are for RW020 ELISA Titers (RW020 Env is homologous to the Ad26 Env insert) and the two right boxes are for UG37 ELISA Titers (UG37 Env is 81.2% homologous to the Ad35 Env insert). Boxes represent the 1^st and 3^rd quartiles (IQR). Red lines indicate median titer. Whiskers extend to the 5^th and 95^th percentiles.

Figure 4. Distribution of IFNγ ELISpot responses 2 and 4 weeks after the second vaccination

A) Ad26.EnvA (RW020 Env peptide pool); B) Ad35-Env P1 (TZA173 Env peptide pool 1); C) Ad35-Env P2 (TZA173 Env peptide pool 2). X-axis shows study group (treatment), percent (%) and frequency (n) of positive responses. Week 2 and 4 samples were analyzed at HIL and BIDMC respectively. Second vaccinations were at month 6 in Groups A and B, and month 3 otherwise. All responses are background-subtracted. Mean responses <1 were set to 1. Boxes show median and IQR. Whiskers extend to the 5^th and 95^th percentiles. Black and Red dots represent negative and positive responses, respectively.

Figure 4. Distribution of IFNγ ELISpot responses 2 and 4 weeks after the second vaccination

A) Ad26.EnvA (RW020 Env peptide pool); B) Ad35-Env P1 (TZA173 Env peptide pool 1); C) Ad35-Env P2 (TZA173 Env peptide pool 2). X-axis shows study group (treatment), percent (%) and frequency (n) of positive responses. Week 2 and 4 samples were analyzed at HIL and BIDMC respectively. Second vaccinations were at month 6 in Groups A and B, and month 3 otherwise. All responses are background-subtracted. Mean responses <1 were set to 1. Boxes show median and IQR. Whiskers extend to the 5^th and 95^th percentiles. Black and Red dots represent negative and positive responses, respectively.

Figure 4. Distribution of IFNγ ELISpot responses 2 and 4 weeks after the second vaccination

A) Ad26.EnvA (RW020 Env peptide pool); B) Ad35-Env P1 (TZA173 Env peptide pool 1); C) Ad35-Env P2 (TZA173 Env peptide pool 2). X-axis shows study group (treatment), percent (%) and frequency (n) of positive responses. Week 2 and 4 samples were analyzed at HIL and BIDMC respectively. Second vaccinations were at month 6 in Groups A and B, and month 3 otherwise. All responses are background-subtracted. Mean responses <1 were set to 1. Boxes show median and IQR. Whiskers extend to the 5^th and 95^th percentiles. Black and Red dots represent negative and positive responses, respectively.

Figure 5. Ad26 and Ad35 neutralizing titers

Individual Ad26 and Ad35 neutralizing antibody responses from volunteers at baseline and 4 weeks post first and second vaccination are shown. Second vaccinations were at month 6 in Groups A and B, and month 3 otherwise. White/orange boxes represent negative/positive baseline Ad26 (top panel) and Ad35 (bottom panel) neutralizing antibodies. Boxes represent median, IQR and the 5^th + 95^th percentiles of the titer distribution. On the x-axis, B, 1 & 2 represent baseline and 4 weeks post first and second vaccinations respectively. Placebo responses represent the proportion of volunteers with a positive titer at any time.