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. 2024 Sep 20;4(9):e0003319.
doi: 10.1371/journal.pgph.0003319. eCollection 2024.

Safety and immunogenicity after a 30-month boost of a subtype C ALVAC-HIV (vCP2438) vaccine prime plus bivalent subtype C gp120/MF59 vaccine boost (HVTN 100): A phase 1-2 randomized double-blind placebo-controlled trial

Vimla Naicker  1 , Fatima Laher  2 , Linda-Gail Bekker  3 , Kelly E Seaton  4 , Mary Allen  5 , Stephen De Rosa  6 , Nicole L Yates  4 , Nonhlanhla N Mkhize  7   8 , Kevin Saunders  4 , Jack Heptinstall  4 , Mookho Malahleha  9 , Kathryn Mngadi  10 , Brodie Daniels  1 , Craig Innes  11 , Chenchen Yu  6 , Tandile Modise  7   8 , Valerie Bekker  7   8 , Nicole Grunenberg  6 , Briana Furch  6 , Maurine D Miner  6 , Sanjay Phogat  12   13 , Carlos A Diazgranados  12 , Sanjay Gurunathan  12 , Marguerite Koutsoukos  13 , Olivier Van Der Meeren  14 , Alison C Roxby  6   15 , Guido Ferrari  16 , Lynn Morris  7   8   10 , David Montefiori  4 , M Juliana McElrath  6 , Georgia D Tomaras  4 , Zoe Moodie  6
Affiliations

Safety and immunogenicity after a 30-month boost of a subtype C ALVAC-HIV (vCP2438) vaccine prime plus bivalent subtype C gp120/MF59 vaccine boost (HVTN 100): A phase 1-2 randomized double-blind placebo-controlled trial

Vimla Naicker et al. PLOS Glob Public Health. .

Abstract

Induction of broad, durable immune responses is a challenge in HIV vaccine development. HVTN 100 Part A administered subtype C-containing ALVAC-HIV at months 0 and 1, and ALVAC-HIV with bivalent subtype C gp120/MF59 at months 3, 6 and 12. As IgG binding antibody and T-cell responses were similar or greater at month 12.5 vs. month 6.5, but waned by month 18, we investigated vaccine-elicited immune responses after a month 30 boost in this study, HVTN 100 Part B. From 13 September 2017 to 7 August 2018, a subgroup of vaccinees was randomized to receive intramuscular injections of ALVAC+gp120/MF59 (n = 32) or gp120/MF59 alone (n = 31) and a subgroup of placebo recipients was administered placebo (n = 7) at month 30. Primary outcomes were safety, IgG binding antibodies (bAbs) to vaccine-specific and V1V2 Env proteins and vaccine-specific CD4+ T cells at month 30.5. Secondary outcomes included neutralizing and antibody dependent cellular cytotoxicity functions and durability at months 30 and 36. Both vaccine groups had an acceptable safety profile. There were no statistically significant differences in the occurrence or level of IgG bAbs between the vaccine boost groups for any vaccine-specific or V1V2 antigens. IgG responses were higher to vaccine-matched gp120 than to V1V2. The booster vaccination restored the magnitude-breadth IgG bAb response to V1V2 antigens at month 30.5. However, it rapidly waned by month 36. CD4+ T-cell response rates to the 3 vaccine-matched Env antigens for the combined vaccine groups ranged from 37% at month 30, boosted to as high as 91% at month 30.5, and waned by month 36 to as low as 44%, with no significant differences between the vaccine boost groups. Because these responses waned after 6 months, additional strategies may be needed to maintain the durability of prime-boost vaccine regimens and to generate these or other immune responses that confer protection. Trial registration: South African National Clinical Trials Register (SANCTR number: DOH-27-0215-4796) and ClinicalTrials.gov (NCT02404311).

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Conflict of interest statement

I have read the journal’s policy and the authors of this manuscript have the following competing interests: The HVTN 100 clinical trial was funded by the National Institute of Allergy and Infectious Diseases (NIAID, https://www.niaid.nih.gov/) U.S. Public Health Service Grants UM1 AI068614 [LOC: HIV Vaccine Trials Network], UM1 AI068618 [LC: HIV Vaccine Trials Network], and UM1 AI068635 [SDMC: HIV Vaccine Trials Network], UM1 AI069453 [Soweto-Bara Clinical Research Site], UM1 AI069519 [Cape Town – Emavundleni Clinical Research Site], UM1 AI069469 [Durban –eThekwini Clinical Research Site], and UM1 AI069422 [Durban – Isipingo Clinical Research Site] and NIH (P30 AI064518). Dr Naicker was supported by a Scientific Leadership Development award from HVTN. The HVTN 100 clinical trial was also funded by the Bill & Melinda Gates Foundation award OPP1110792. The Gates Foundation provided funding to Fred Hutchinson Cancer Center to support the implementation of HVTN 100 at the Soweto-Bara Clinical Research Site, Cape Town-Emavundleni Clinical Research Site, Durban-eThekwini Clinical Research Site, and Durban-Isipingo Clinical Research Site, as well as the Klerksdorp and Soshanguve sites. Funding was provided to Novartis Vaccines and Diagnostics (now part of the GlaxoSmithKline group of companies) by NIAID (HHSN272201300033C//HHSN272201600012C) for the selection and process development of the two gp120 envelope proteins TV1.C and 1086.C, and by the Bill & Melinda Gates Foundation Global Health Grant OPP1017604 and NIAID for the manufacture and release of the gp120 clinical grade material. Role of the funding source: Within the terms of the Grant Award of the Cooperative Agreement with the HIV Vaccine Trials Network (HVTN), the study sponsor, NIAID, contributed to, reviewed, and approved the HVTN 100 study design, contributed to the review and analysis of data, concurred with the decision to publish, and assisted with the preparation of the manuscript. The Gates Foundation contributed to, reviewed, and approved the HVTN 100 study design, and reviewed the data from the study. Neither NIAID or the Gates Foundation were involved in the data collection, and did not perform statistical analyses. GlaxoSmithKline Biologicals SA was provided the opportunity to review a preliminary version of this manuscript, but the authors are solely responsible for final content and interpretation. MK is employed by and holds shares in GSK. All other authors have nothing to declare.

Figures

Fig 1
Fig 1. CONSORT diagram.
SPA = study product administration; bAb = binding antibody; ICS = intracellular cytokine staining; ADCC = antibody dependent cellular cytotoxicity; nAb = neutralizing antibody.
Fig 2
Fig 2
IgG binding antibody responses to the V1V2 vaccine strain antigens: 1086 (A), TV1 (B) and ZM 96 (C). Response rates and magnitudes of IgG binding antibodies to the V1V2 vaccine strain antigens: 1086 (A), TV1 (B) and ZM96 (C) among per-protocol vaccine recipients of HVTN 100 Part B. Boxplots show magnitude as mean fluorescent intensity (MFI) responses to individual V1V2 antigens and are based on positive responders, shown as solid circles, negative responders are shown as grey triangles. The box represents the interquartile range and distribution of data with the horizontal line in the box representing the median. The top and bottom whisker represents the maximum and minimum value that is not an outlier respectively.
Fig 3
Fig 3
Magnitude-breadth of IgG binding antibody responses subtype C env V1V2 (A-C), gp120 (D-F) and gp140 (G-I) antigens among participants in the cohort for Part B at the Month 30 vaccination timepoint (A,D,G), 2 weeks after the Month 30 vaccination (Month 30.5) (B,E,H) and at Month 36 (C,F,I). Panel size is 15 (A-C), 7 (D,F), 6 (E), and 8 (G-I). AUC = area under curve, T = treatment, P = placebo, MFI = mean fluorescence intensity. T1a = ALVAC + gp120/MF59; T1b = gp120/MF49 alone.
Fig 4
Fig 4. Summary of the response rates and magnitudes of CD4+ T cell responses.
Boxplots show response magnitude in the percent expression of CD4+IFN-gamma and/or IL-2 and/or CD40L T cell responses to Env 1086 (A), TV1 (B) and ZM96 (C) and are based on positive responders, shown as solid circles, and negative responders are shown as grey triangles.
See this image and copyright information in PMC

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