RV144 HIV-1 vaccination impacts post-infection antibody responses

The RV144 vaccine efficacy clinical trial showed a reduction in HIV-1 infections by 31%. Vaccine efficacy was associated with stronger binding antibody responses to the HIV Envelope (Env) V1V2 region, with decreased efficacy as responses wane. High levels of Ab-dependent cellular cytotoxicity (ADCC) together with low plasma levels of Env-specific IgA also correlated with decreased infection risk. We investigated whether B cell priming from RV144 vaccination impacted functional antibody responses to HIV-1 following infection. Antibody responses were assessed in 37 vaccine and 63 placebo recipients at 6, 12, and 36 months following HIV diagnosis. The magnitude, specificity, dynamics, subclass recognition and distribution of the binding antibody response following infection were different in RV144 vaccine recipients compared to placebo recipients. Vaccine recipients demonstrated increased IgG1 binding specifically to V1V2, as well as increased IgG2 and IgG4 but decreased IgG3 to HIV-1 Env. No difference in IgA binding to HIV-1 Env was detected between the vaccine and placebo recipients following infection. RV144 vaccination limited the development of broadly neutralizing antibodies post-infection, but enhanced Fc-mediated effector functions indicating B cell priming by RV144 vaccination impacted downstream antibody function. However, these functional responses were not associated with clinical markers of disease progression. These data reveal that RV144 vaccination primed B cells towards specific binding and functional antibody responses following HIV-1 infection.

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Comprehensive Sieve Analysis of Breakthrough HIV-1 Sequences in the RV144 Vaccine Efficacy Trial

PLoS Computational Biology ◽

10.1371/journal.pcbi.1003973 ◽

2015 ◽

Vol 11 (2) ◽

pp. e1003973 ◽

Cited By ~ 38

Author(s):

Paul T. Edlefsen ◽

Morgane Rolland ◽

Tomer Hertz ◽

Sodsai Tovanabutra ◽

Andrew J. Gartland ◽

...

Keyword(s):

Vaccine Efficacy ◽

Sieve Analysis ◽

Efficacy Trial ◽

Hiv 1 ◽

Rv144 Vaccine

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Frequencies of circulating Th1-biased T follicular helper cells in acute HIV-1 infection correlate with the development of HIV-specific antibody responses and lower set point viral load

10.1101/304329 ◽

2018 ◽

Cited By ~ 1

Author(s):

Omolara Baiyegunhi ◽

Bongiwe Ndlovu ◽

Funsho Ogunshola ◽

Nasreen Ismail ◽

Bruce D. Walker ◽

...

Keyword(s):

Viral Load ◽

Neutralizing Antibodies ◽

Acute Infection ◽

Antibody Responses ◽

Set Point ◽

Follicular Helper ◽

Clade C ◽

Acute Hiv ◽

Anti Hiv ◽

Hiv 1

AbstractDespite decades of focused research, the field has yet to develop a prophylactic vaccine. In the RV144 vaccine trial, non-neutralizing antibody responses were identified as a correlate for prevention of HIV acquisition. However, factors that predict the development of such antibodies are not fully elucidated. We sought to define the contribution of circulating T follicular helper (cTfh) cell subsets to the development of non-neutralizing antibodies in HIV-1 clade C infection. Study participants were recruited from an acute HIV-1 clade C infection cohort. Plasma anti-gp41, -gp120, -p24 and -p17 antibodies were screened using a customized multivariate Luminex assay. Phenotypic and functional characterization of cTfh were performed using HLA class II tetramers and intracellular cytokine staining. In this study, we found that acute HIV-1 clade C infection skewed differentiation of functional cTfh subsets towards increased Tfh1 (p=0.02) and Tfh2 (p<0.0001) subsets, with a concomitant decrease in overall Tfh1-17 (that shares both Tfh1 and Tfh17 properties) (p=0.01) and Tfh17 subsets (p<0.0001) compared to HIV negative subjects. Interestingly, the frequencies of Tfh1 during acute infection (5.0-8.0 weeks post-infection) correlated negatively with set point viral load (p=0.03, r=-60) and were predictive of p24-specific plasma IgG titers at one year of infection (p=0.003, r=0.85). Taken together, our results suggest that circulating the Tfh1 subset plays an important role in the development of anti-HIV antibody responses and contributes to HIV suppression during acute HIV-1 infection. These results have implications for vaccine studies aimed at inducing long lasting anti-HIV antibody responses.ImportanceThe HIV epidemic in southern Africa accounts for almost half of the global HIV burden with HIV-1 clade C being the predominant strain. It is therefore important to define immune correlates of clade C HIV control that might have implications for vaccine design in this region. T follicular helper (Tfh) cells are critical for the development of HIV-specific antibody responses and could play a role in viral control. Here we showed that the early induction of circulating Tfh1 cells during acute infection correlated positively with the magnitude of p24-specific IgG and was associated with lower set point viral load. This study highlights a key Tfh cell subset that could limit HIV replication by enhancing antibody generation. This study underscores the importance of circulating Tfh cells in promoting non-neutralizing antibodies during HIV-1 infection.

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Neutralizing Antibody Responses in Acute Human Immunodeficiency Virus Type 1 Subtype C Infection

Journal of Virology ◽

10.1128/jvi.00239-07 ◽

2007 ◽

Vol 81 (12) ◽

pp. 6187-6196 ◽

Cited By ~ 209

Author(s):

E. S. Gray ◽

P. L. Moore ◽

I. A. Choge ◽

J. M. Decker ◽

F. Bibollet-Ruche ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Neutralizing Antibodies ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Subtype C ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT The study of the evolution and specificities of neutralizing antibodies during the course of human immunodeficiency virus type 1 (HIV-1) infection may be important in the discovery of possible targets for vaccine design. In this study, we assessed the autologous and heterologous neutralization responses of 14 HIV-1 subtype C-infected individuals, using envelope clones obtained within the first 2 months postinfection. Our data show that potent but relatively strain-specific neutralizing antibodies develop within 3 to 12 months of HIV-1 infection. The magnitude of this response was associated with shorter V1-to-V5 envelope lengths and fewer glycosylation sites, particularly in the V1-V2 region. Anti-MPER antibodies were detected in 4 of 14 individuals within a year of infection, while antibodies to CD4-induced (CD4i) epitopes developed to high titers in 12 participants, in most cases before the development of autologous neutralizing antibodies. However, neither anti-MPER nor anti-CD4i antibody specificity conferred neutralization breadth. These data provide insights into the kinetics, potency, breadth, and epitope specificity of neutralizing antibody responses in acute HIV-1 subtype C infection.

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Nanoparticle Vaccines for Inducing HIV-1 Neutralizing Antibodies

Vaccines ◽

10.3390/vaccines7030076 ◽

2019 ◽

Vol 7 (3) ◽

pp. 76 ◽

Cited By ~ 15

Author(s):

Mitch Brinkkemper ◽

Kwinten Sliepen

Keyword(s):

Envelope Glycoprotein ◽

Neutralizing Antibodies ◽

Critical Role ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Broadly Neutralizing Antibodies ◽

Viral Membrane ◽

Immunodeficiency Virus ◽

Hiv 1

The enormous sequence diversity between human immunodeficiency virus type 1 (HIV-1) strains poses a major roadblock for generating a broadly protective vaccine. Many experimental HIV-1 vaccine efforts are therefore aimed at eliciting broadly neutralizing antibodies (bNAbs) that are capable of neutralizing the majority of circulating HIV-1 strains. The envelope glycoprotein (Env) trimer on the viral membrane is the sole target of bNAbs and the key component of vaccination approaches aimed at eliciting bNAbs. Multimeric presentation of Env on nanoparticles often plays a critical role in these strategies. Here, we will discuss the different aspects of nanoparticles in Env vaccination, including recent insights in immunological processes underlying their perceived advantages, the different nanoparticle platforms and the various immunogenicity studies that employed nanoparticles to improve (neutralizing) antibody responses against Env.

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A Replicating Single-Cycle Adenovirus Vaccine Effective against Clostridium difficile

Vaccines ◽

10.3390/vaccines8030470 ◽

2020 ◽

Vol 8 (3) ◽

pp. 470

Author(s):

William E. Matchett ◽

Stephanie Anguiano-Zarate ◽

Goda Baddage Rakitha Malewana ◽

Haley Mudrick ◽

Melissa Weldy ◽

...

Keyword(s):

Clostridium Difficile ◽

Neutralizing Antibodies ◽

Antibody Responses ◽

Complete Protection ◽

Single Cycle ◽

Toxin B ◽

Toxin Binding ◽

Binding Domains ◽

Binding Antibody

Clostridium difficile causes nearly 500,000 infections and nearly 30,000 deaths each year in the U.S., which is estimated to cost $4.8 billion. C. difficile infection (CDI) arises from bacteria colonizing the large intestine and releasing two toxins, toxin A (TcdA) and toxin B (TcdB). Generating humoral immunity against C. difficile’s toxins provides protection against primary infection and recurrence. Thus, a vaccine may offer the best opportunity for sustained, long-term protection. We developed a novel single-cycle adenovirus (SC-Ad) vaccine against C. difficile expressing the receptor-binding domains from TcdA and TcdB. The single immunization of mice generated sustained toxin-binding antibody responses and protected them from lethal toxin challenge for up to 38 weeks. Immunized Syrian hamsters produced significant toxin-neutralizing antibodies that increased over 36 weeks. Single intramuscular immunization provided complete protection against lethal BI/NAP1/027 spore challenge 45 weeks later. These data suggest that this replicating vaccine may prove useful against CDI in humans.

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Immunogenicity, safety, and efficacy of sequential immunizations with an SIV-based IDLV expressing CH505 Envs

npj Vaccines ◽

10.1038/s41541-020-00252-w ◽

2020 ◽

Vol 5 (1) ◽

Author(s):

Maria Blasi ◽

Donatella Negri ◽

Kevin O. Saunders ◽

Erich J. Baker ◽

Hannah Stadtler ◽

...

Keyword(s):

Immune Responses ◽

Neutralizing Antibodies ◽

Lentiviral Vector ◽

Rhesus Macaques ◽

Infected Individual ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Safety And Efficacy ◽

Env Protein ◽

Hiv 1

AbstractA preventative HIV-1 vaccine is an essential intervention needed to halt the HIV-1 pandemic. Neutralizing antibodies protect against HIV-1 infection in animal models, and thus an approach toward a protective HIV-1 vaccine is to induce broadly cross-reactive neutralizing antibodies (bnAbs). One strategy to achieve this goal is to define envelope (Env) evolution that drives bnAb development in infection and to recreate those events by vaccination. In this study, we report the immunogenicity, safety, and efficacy in rhesus macaques of an SIV-based integrase defective lentiviral vector (IDLV) expressing sequential gp140 Env immunogens derived from the CH505 HIV-1-infected individual who made the CH103 and CH235 bnAb lineages. Immunization with IDLV expressing sequential CH505 Envs induced higher magnitude and more durable binding and neutralizing antibody responses compared to protein or DNA +/− protein immunizations using the same sequential envelopes. Compared to monkeys immunized with a vector expressing Envs alone, those immunized with the combination of IDLV expressing Env and CH505 Env protein demonstrated improved durability of antibody responses at six months after the last immunization as well as lower peak viremia and better virus control following autologous SHIV-CH505 challenge. There was no evidence of vector mobilization or recombination in the immunized and challenged monkeys. Although the tested vaccines failed to induce bnAbs and to mediate significant protection following SHIV-challenge, our results show that IDLV proved safe and successful at inducing higher titer and more durable immune responses compared to other vaccine platforms.

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Comprehensive Sieve Analysis of Breakthrough HIV-1 Sequences in the RV144 Vaccine Efficacy Trial

AIDS Research and Human Retroviruses ◽

10.1089/aid.2014.5036.abstract ◽

2014 ◽

Vol 30 (S1) ◽

pp. A25-A26

Author(s):

Paul T. Edlefsen ◽

Morgane Rolland ◽

Tomer Hertz ◽

Sodsai Tovanabutra ◽

Andrew J. Gartland ◽

...

Keyword(s):

Vaccine Efficacy ◽

Sieve Analysis ◽

Efficacy Trial ◽

Hiv 1 ◽

Rv144 Vaccine

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Viral Phenotypes and Antibody Responses in Long-Term Survivors Infected with Attenuated Human Immunodeficiency Virus Type 1 Containing Deletions in the nef and Long Terminal Repeat Regions

Journal of Virology ◽

10.1128/jvi.00650-07 ◽

2007 ◽

Vol 81 (17) ◽

pp. 9268-9278 ◽

Cited By ~ 14

Author(s):

Erin E. Verity ◽

Dimitra Zotos ◽

Kim Wilson ◽

Catherine Chatfield ◽

Victoria A. Lawson ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Neutralizing Antibodies ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Wild Type Virus ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT The Sydney Blood Bank Cohort (SBBC) consists of eight blood transfusion recipients infected with nef-attenuated human immunodeficiency virus type 1 (HIV-1) acquired from a single donor. Here, we show that viral phenotypes and antibody responses differ considerably between individual cohort members, despite the single source of infection. Replication of isolated virus varied from barely detectable to similar to that of the wild-type virus, and virus isolated from five SBBC members showed coreceptor usage signatures unique to each individual. Higher viral loads and stronger neutralizing antibody responses were associated with better-replicating viral strains, and detectable viral replication was essential for the development of strong and sustained humoral immune responses. Despite the presence of strong neutralizing antibodies in a number of SBBC members, disease progression was not prevented, and each cohort member studied displayed a unique outcome of infection with nef-attenuated HIV-1.

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Covalent Linkage of HIV-1 Trimers to Synthetic Liposomes Elicits Improved B Cell and Antibody Responses

Journal of Virology ◽

10.1128/jvi.00443-17 ◽

2017 ◽

Vol 91 (16) ◽

Cited By ~ 31

Author(s):

Shridhar Bale ◽

Geraldine Goebrecht ◽

Armando Stano ◽

Richard Wilson ◽

Takayuki Ota ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Germinal Center ◽

Neutralizing Antibodies ◽

Tier 2 ◽

Covalent Linkage ◽

His Tag ◽

Hiv 1

ABSTRACT We have demonstrated that a liposomal array of well-ordered trimers enhances B cell activation, germinal center formation, and the elicitation of tier-2 autologous neutralizing antibodies. Previously, we coupled well-ordered cleavage-independent NFL trimers via their C-terminal polyhistidine tails to nickel lipids integrated into the lipid bilayer. Despite favorable in vivo effects, concern remained over the potentially longer-term in vivo instability of noncovalent linkage of the trimers to the liposomes. Accordingly, we tested both cobalt coupling and covalent linkage of the trimers to the liposomes by reengineering the polyhistidine tail to include a free cysteine on each protomer of model BG505 NFL trimers to allow covalent linkage. Both cobalt and cysteine coupling resulted in a high-density array of NFL trimers that was stable in both 20% mouse serum and 100 mM EDTA, whereas the nickel-conjugated trimers were not stable under these conditions. Binding analysis and calcium flux with anti-Env-specific B cells confirmed that the trimers maintained conformational integrity following coupling. Following immunization of mice, serologic analysis demonstrated that the covalently coupled trimers elicited Env-directed antibodies in a manner statistically significantly improved compared to soluble trimers and nickel-conjugated trimers. Importantly, the covalent coupling not only enhanced gp120-directed responses compared to soluble trimers, it also completely eliminated antibodies directed to the C-terminal His tag located at the “bottom” of the spike. In contrast, soluble and noncovalent formats efficiently elicited anti-His tag antibodies. These data indicate that covalent linkage of well-ordered trimers to liposomes in high-density array displays multiple advantages in vitro and in vivo. IMPORTANCE Enveloped viruses typically encode a surface-bound glycoprotein that mediates viral entry into host cells and is a primary target for vaccine design. Liposomes with modified lipid head groups have a unique feature of capturing and displaying antigens on their surfaces, mimicking the native pathogens. Our first-generation nickel-based liposomes captured HIV-1 Env glycoprotein trimers via a noncovalent linkage with improved efficacy over soluble glycoprotein in activating germinal center B cells and eliciting tier-2 autologous neutralizing antibodies. In this study, we report the development of second-generation cobalt- and maleimide-based liposomes that have improved in vitro stability over nickel-based liposomes. In particular, the maleimide liposomes captured HIV-1 Env trimers via a more stable covalent bond, resulting in enhanced germinal center B cell responses that generated higher antibody titers than the soluble trimers and liposome-bearing trimers via noncovalent linkages. We further demonstrate that covalent coupling prevents release of the trimers prior to recognition by B cells and masks a nonneutralizing determinant located at the bottom of the trimer.

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