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Adjuvanted HIV-1 vaccine promotes antibody-dependent phagocytic responses and protects against heterologous SHIV challenge.

ABSTRACT: To augment HIV-1 pox-protein vaccine immunogenicity using a next generation adjuvant, a prime-boost strategy of recombinant modified vaccinia virus Ankara and multimeric Env gp145 was evaluated in macaques with either aluminum (alum) or a novel liposomal monophosphoryl lipid A (MPLA) formulation adsorbed to alum, ALFA. Binding antibody responses were robust and comparable between arms, while antibody-dependent neutrophil and monocyte phagocytotic responses were greatly enhanced by ALFA. Per-exposure vaccine efficacy against heterologous tier 2 SHIV mucosal challenge was 90% in ALFA-adjuvanted males (P = 0.002), while alum conferred no protection. Half of the ALFA-adjuvanted males remained uninfected after the full challenge series, which spanned seven months after the last vaccination. Antibody-dependent monocyte and neutrophil phagocytic responses both strongly correlated with protection. Significant sex differences in infection risk were observed, with much lower infection rates in females than males. In humans, MPLA-liposome-alum adjuvanted gp120 also increased HIV-1-specific phagocytic responses relative to alum. Thus, next-generation liposome-based adjuvants can drive vaccine elicited antibody effector activity towards potent phagocytic responses in both macaques and humans and these responses correlate with protection. Future protein vaccination strategies aiming to improve functional humoral responses may benefit from such adjuvants.

SUBMITTER: Om K

PROVIDER: S-EPMC7505435 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Adjuvanted HIV-1 vaccine promotes antibody-dependent phagocytic responses and protects against heterologous SHIV challenge.

Om Kier K Paquin-Proulx Dominic D Montero Maria M Peachman Kristina K Shen Xiaoying X Wieczorek Lindsay L Beck Zoltan Z Weiner Joshua A JA Kim Dohoon D Li Yifan Y Mdluli Thembi T Shubin Zhanna Z Bryant Christopher C Sharma Vishakha V Tokarev Andrey A Dawson Peter P White Yohann Y Appelbe Oliver O Klatt Nichole R NR Tovanabutra Sodsai S Estes Jacob D JD Matyas Gary R GR Ferrari Guido G Alving Carl R CR Tomaras Georgia D GD Ackerman Margaret E ME Michael Nelson L NL Robb Merlin L ML Polonis Victoria V Rolland Morgane M Eller Michael A MA Rao Mangala M Bolton Diane L DL

PLoS pathogens 20200903 9

To augment HIV-1 pox-protein vaccine immunogenicity using a next generation adjuvant, a prime-boost strategy of recombinant modified vaccinia virus Ankara and multimeric Env gp145 was evaluated in macaques with either aluminum (alum) or a novel liposomal monophosphoryl lipid A (MPLA) formulation adsorbed to alum, ALFA. Binding antibody responses were robust and comparable between arms, while antibody-dependent neutrophil and monocyte phagocytotic responses were greatly enhanced by ALFA. Per-expo ...[more]

PMID: 32881968

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Project description:BackgroundPassive transfer of antibodies can be protective in the simian human immunodeficiency virus (SHIV)--rhesus macaque challenge model. The human monoclonal antibody IgG1 b12 neutralizes human immunodeficiency type 1 (HIV-1) in vitro and protects against challenge by SHIV. Our hypothesis is that neutralizing antibodies can only completely inactivate a relatively small number of infectious virus.Methods and findingsWe have used GHOST cell assays to quantify individual infectious events with HIV-1SF162 and its SHIV derivatives: the relatively neutralization sensitive SHIV(SF162P4) isolate and the more resistant SHIV(SF162P3). A plot of the number of fluorescent GHOST cells with increasing HIV-1SF162 dose is not linear. It is likely that with high-dose inocula, infection with multiple virus produces additive fluorescence in individual cells. In studies of the neutralization kinetics of IgG1 b12 against these isolates, events during the absorption phase of the assay, as well as the incubation phase, determine the level of neutralization. It is possible that complete inactivation of a virus is limited to the time it is exposed on the cell surface. Assays can be modified so that neutralization of these very low doses of virus can be quantified. A higher concentration of antibody is required to neutralize the same dose of resistant SHIV(SF162P3) than the sensitive SHIV(SF162P4). In the absence of selection during passage, the density of the CCR5 co-receptor on the GHOST cell surface is reduced. Changes in the CD4 : CCR5 density ratio influence neutralization.ConclusionsLow concentrations of IgG1 b12 completely inactivate small doses of the neutralization resistant SHIV(SF162P3). Assays need to be modified to quantify this effect. Results from modified assays may predict protection following repeated low-dose shiv challenges in rhesus macaques. It should be possible to induce this level of antibody by vaccination so that modified assays could predict the outcome of human trials.

Dataset Information

Adjuvanted HIV-1 vaccine promotes antibody-dependent phagocytic responses and protects against heterologous SHIV challenge.

Publications

Adjuvanted HIV-1 vaccine promotes antibody-dependent phagocytic responses and protects against heterologous SHIV challenge.

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