Faculty Opinions recommendation of Elicitation of robust tier 2 neutralizing antibody responses in nonhuman primates by HIV envelope trimer immunization using optimized approaches.

ABSTRACT Analysis of breakthrough HIV-1 infections could elucidate whether prior vaccination primes relevant immune responses. Here, we measured HIV-specific antibody responses in 14 South African volunteers who acquired HIV infection after participating in phase 1/2 trials of envelope-containing immunogens. Serum samples were collected annually following HIV-1 infection from participants in trials HVTN 073 (subtype C, DNA/MVA, phase 1 trial, n = 1), HVTN 086 (subtype C, DNA/MVA/gp140 protein, phase 1 trial, n = 2), and HVTN 204 (multisubtype, DNA/adenovirus serotype 5 [Ad5], phase 2 trial, n = 7) and 4 placebo recipients. Binding and neutralizing antibody responses to Env proteins and peptides were determined pre- and post-HIV infection using an enzyme-linked immunosorbent assay and the TZM-bl cell neutralization assay, respectively. HIV-infected South African individuals served as unvaccinated controls. Binding antibodies to gp41, V3, V2, the membrane-proximal external region (MPER), and the CD4 binding site were detected from the first year of HIV-1 subtype C infection, and the levels were similar in vaccinated and placebo recipients. Neutralizing antibody responses against tier 1A viruses were detected in all participants, with the highest titers being to a subtype C virus, MW965.26. No responses were observed just prior to infection, indicating that vaccine-primed HIV-specific antibodies had waned. Sporadic neutralization activity against tier 2 isolates was observed after 2 to 3 years of HIV infection, but these responses were similar in the vaccinated and placebo groups as well as the unvaccinated controls. Our data suggest that prior vaccination with these immunogens did not alter the antibody responses to HIV-1 infection, nor did it accelerate the development of HIV neutralization breadth. IMPORTANCE There is a wealth of information on HIV-specific vaccine-induced immune responses among HIV-uninfected participants; however, data on immune responses among participants who acquire HIV after vaccination are limited. Here we show that HIV-specific binding antibody responses in individuals with breakthrough HIV infections were not affected by prior vaccination with HIV envelope-containing immunogens. We also found that these vectored vaccines did not prime tier 2 virus-neutralizing antibody responses, which are thought to be required for prevention against HIV acquisition, or accelerate the development of neutralization breadth. Although this study is limited, such studies can provide insights into whether vaccine-elicited antibody responses are boosted by HIV infection to acquire broader neutralizing activity, which may help to identify antigens relevant to the design of more effective vaccines.

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Vaccine-Induced Protection from Homologous Tier 2 SHIV Challenge in Nonhuman Primates Depends on Serum-Neutralizing Antibody Titers

Immunity ◽

10.1016/j.immuni.2018.11.011 ◽

2019 ◽

Vol 50 (1) ◽

pp. 241-252.e6 ◽

Cited By ~ 57

Author(s):

Matthias G. Pauthner ◽

Joseph P. Nkolola ◽

Colin Havenar-Daughton ◽

Ben Murrell ◽

Samantha M. Reiss ◽

...

Keyword(s):

Nonhuman Primates ◽

Neutralizing Antibody ◽

Tier 2 ◽

Antibody Titers

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Achieving Potent Autologous Neutralizing Antibody Responses against Tier 2 HIV-1 Viruses by Strategic Selection of Envelope Immunogens

The Journal of Immunology ◽

10.4049/jimmunol.1500527 ◽

2016 ◽

Vol 196 (7) ◽

pp. 3064-3078 ◽

Cited By ~ 34

Author(s):

Ann J. Hessell ◽

Delphine C. Malherbe ◽

Franco Pissani ◽

Sean McBurney ◽

Shelly J. Krebs ◽

...

Keyword(s):

Neutralizing Antibody ◽

Antibody Responses ◽

Tier 2 ◽

Hiv 1 ◽

Selection Of

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Neutralizing antibody responses to an HIV envelope glycan hole are not easily broadened

10.1101/827477 ◽

2019 ◽

Cited By ~ 1

Author(s):

Yuhe R. Yang ◽

Laura E. McCoy ◽

Marit J. van Gils ◽

Raiees Andrabi ◽

Hannah L. Turner ◽

...

Keyword(s):

High Resolution ◽

Neutralizing Antibodies ◽

Neutralizing Antibody ◽

Tier 2 ◽

High Resolution Data ◽

Subtype B ◽

Glycosylation Sites ◽

Antibody Complex ◽

Subtype A ◽

Hiv Envelope

ABSTRACTExtensive studies with subtype A BG505-derived HIV envelope glycoprotein (Env) SOSIP immunogens have revealed that the dominant autologous neutralizing site in rabbits is located in an exposed region of the heavily glycosylated trimer that lacks potential N-linked glycosylation sites at positions 230, 241, and 289. The Env derived from B41, a subtype B virus, shares a glycan hole centered on positions 230 and 289. BG505 and B41 SOSIP immunogens were combined to test whether immunization in rabbits could induce broader Tier 2 neutralizing responses to the common glycan hole shared between BG505 and B41. Here we isolated autologous neutralizing antibodies (nAbs) that were induced by immunization with B41 SOSIP alone, as well as B41 and BG505 co-immunization, and describe their structure in complex with the B41 SOSIP trimer. Our data suggest that distinct autologous nAb lineages are induced by BG505 and B41 immunogens, even when both immunogens were administered together. In contrast to previously described BG505 glycan hole antibodies, the B41-specific nAbs accommodate the highly conserved N241 glycan (>97% conserved), which is present in B41. Single particle cryo-electron microscopy (cryoEM) studies confirmed that B41 and BG505-specific nAbs bind to overlapping glycan hole epitopes. In an attempt to broaden the reactivity of a B41-specific nAb, mutations in the BG505 glycan hole epitope guided by our high-resolution data only recovered partial binding. Overall, designing prime-boost immunogens to increase the breath of nAb responses directed at glycan holes epitopes remains challenging even when the typically immunodominant glycan holes despite overlap with different Envs.IMPORTANCEA glycan hole is one of the most dominant autologous neutralizing epitopes targeted on BG505 and B41 SOSIP trimer immunized rabbits. Our high-resolution cryoEM studies of B41 in complex with a B41-specific antibody complex elucidate the molecular basis of this strain-specific glycan hole response. We conclude that eliciting cross-reactive responses to this region would likely require hybrid immunogens that bridge between BG505 and B41.

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Ad26 vaccine protects against SARS-CoV-2 severe clinical disease in hamsters

Nature Medicine ◽

10.1038/s41591-020-1070-6 ◽

2020 ◽

Vol 26 (11) ◽

pp. 1694-1700 ◽

Cited By ~ 12

Author(s):

Lisa H. Tostanoski ◽

Frank Wegmann ◽

Amanda J. Martinot ◽

Carolin Loos ◽

Katherine McMahan ◽

...

Keyword(s):

Weight Loss ◽

Nonhuman Primates ◽

Severe Pneumonia ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Clinical Disease ◽

High Dose ◽

Preclinical Studies ◽

Vaccine Protection ◽

Adenovirus Serotype

AbstractCoronavirus disease 2019 (COVID-19) in humans is often a clinically mild illness, but some individuals develop severe pneumonia, respiratory failure and death1–4. Studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in hamsters5–7 and nonhuman primates8–10 have generally reported mild clinical disease, and preclinical SARS-CoV-2 vaccine studies have demonstrated reduction of viral replication in the upper and lower respiratory tracts in nonhuman primates11–13. Here we show that high-dose intranasal SARS-CoV-2 infection in hamsters results in severe clinical disease, including high levels of virus replication in tissues, extensive pneumonia, weight loss and mortality in a subset of animals. A single immunization with an adenovirus serotype 26 vector-based vaccine expressing a stabilized SARS-CoV-2 spike protein elicited binding and neutralizing antibody responses and protected against SARS-CoV-2-induced weight loss, pneumonia and mortality. These data demonstrate vaccine protection against SARS-CoV-2 clinical disease. This model should prove useful for preclinical studies of SARS-CoV-2 vaccines, therapeutics and pathogenesis.

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Neutralizing antibody responses to subtype B and C adjuvanted HIV envelope protein vaccination in rabbits

Virology ◽

10.1016/j.virol.2009.02.005 ◽

2009 ◽

Vol 387 (1) ◽

pp. 147-156 ◽

Cited By ~ 28

Author(s):

Brian Burke ◽

Victor Raúl Gómez-Román ◽

Ying Lian ◽

Yide Sun ◽

Elaine Kan ◽

...

Keyword(s):

Envelope Protein ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Subtype B ◽

Hiv Envelope

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Protection against SARS-CoV-2 Beta Variant in mRNA-1273 Boosted Nonhuman Primates

10.1101/2021.08.11.456015 ◽

2021 ◽

Author(s):

Kizzmekia S. Corbett ◽

Matthew Gagne ◽

Danielle Wagner ◽

Sarah O'Connell ◽

Sandeep R. Narpala ◽

...

Keyword(s):

Nonhuman Primates ◽

Geometric Mean ◽

Severe Disease ◽

Neutralizing Antibody ◽

Fold Increase ◽

Primary Response ◽

Antibody Responses ◽

Lower Airway ◽

Memory Time ◽

High Level

Neutralizing antibody responses gradually wane after vaccination with mRNA-1273 against several variants of concern (VOC), and additional boost vaccinations may be required to sustain immunity and protection. Here, we evaluated the immune responses in nonhuman primates that received 100 μg of mRNA-1273 vaccine at 0 and 4 weeks and were boosted at week 29 with mRNA-1273 (homologous) or mRNA-1273.β (heterologous), which encompasses the spike sequence of the B.1.351 (beta or β) variant. Reciprocal ID50 pseudovirus neutralizing antibody geometric mean titers (GMT) against live SARS-CoV-2 D614G and the β variant, were 4700 and 765, respectively, at week 6, the peak of primary response, and 644 and 553, respectively, at a 5-month post-vaccination memory time point. Two weeks following homologous or heterologous boost β-specific reciprocal ID50 GMT were 5000 and 3000, respectively. At week 38, animals were challenged in the upper and lower airway with the β variant. Two days post-challenge, viral replication was low to undetectable in both BAL and nasal swabs in most of the boosted animals. These data show that boosting with the homologous mRNA-1273 vaccine six months after primary immunization provides up to a 20-fold increase in neutralizing antibody responses across all VOC, which may be required to sustain high-level protection against severe disease, especially for at-risk populations.

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Optimization of Non-Coding Regions Improves Protective Efficacy of an mRNA SARS-CoV-2 Vaccine in Nonhuman Primates

10.1101/2021.08.13.456316 ◽

2021 ◽

Author(s):

Makda Gebre ◽

Susanne Rauch ◽

Nicole Roth ◽

Jingyou Yu ◽

Abishek Chandrashekar ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Nonhuman Primates ◽

Protective Efficacy ◽

Neutralizing Antibody ◽

Antigen Expression ◽

Antibody Responses ◽

Partial Protection ◽

Viral Loads ◽

Coding Regions ◽

Cell Responses

The CVnCoV (CureVac) mRNA vaccine for SARS-CoV-2 has recently been evaluated in a phase 2b/3 efficacy trial in humans. CV2CoV is a second-generation mRNA vaccine with optimized non-coding regions and enhanced antigen expression. Here we report a head-to-head study of the immunogenicity and protective efficacy of CVnCoV and CV2CoV in nonhuman primates. We immunized 18 cynomolgus macaques with two doses of 12 ug of lipid nanoparticle formulated CVnCoV, CV2CoV, or sham (N=6/group). CV2CoV induced substantially higher binding and neutralizing antibodies, memory B cell responses, and T cell responses as compared with CVnCoV. CV2CoV also induced more potent neutralizing antibody responses against SARS-CoV-2 variants, including B.1.351 (beta), B.1.617.2 (delta), and C.37 (lambda). While CVnCoV provided partial protection against SARS-CoV-2 challenge, CV2CoV afforded robust protection with markedly lower viral loads in the upper and lower respiratory tract. Antibody responses correlated with protective efficacy. These data demonstrate that optimization of non-coding regions can greatly improve the immunogenicity and protective efficacy of an mRNA SARS-CoV-2 vaccine in nonhuman primates.

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Neutralizing Antibody Responses Induced by HIV-1 Envelope Glycoprotein SOSIP Trimers Derived from Elite Neutralizers

Journal of Virology ◽

10.1128/jvi.01214-20 ◽

2020 ◽

Vol 94 (24) ◽

Author(s):

Anna Schorcht ◽

Tom L. G. M. van den Kerkhof ◽

Christopher A. Cottrell ◽

Joel D. Allen ◽

Jonathan L. Torres ◽

...

Keyword(s):

Envelope Glycoprotein ◽

Neutralizing Antibodies ◽

High Titer ◽

Vaccine Design ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Tier 2 ◽

Broadly Neutralizing Antibodies ◽

Subtype B ◽

Hiv 1

ABSTRACT The induction of broadly neutralizing antibodies (bNAbs) is a major goal in vaccine research. HIV-1-infected individuals that develop exceptionally strong bNAb responses, termed elite neutralizers, can inform vaccine design by providing blueprints for the induction of similar bNAb responses. We describe a new recombinant native-like envelope glycoprotein (Env) SOSIP trimer, termed AMC009, based on the viral founder sequences of an elite neutralizer. The subtype B AMC009 SOSIP protein formed stable native-like trimers that displayed multiple bNAb epitopes. Overall, its structure at 4.3-Å resolution was similar to that of BG505 SOSIP.664. The AMC009 trimer resembled one from a second elite neutralizer, AMC011, in having a dense and complete glycan shield. When tested as immunogens in rabbits, the AMC009 trimers did not induce autologous neutralizing antibody (NAb) responses efficiently while the AMC011 trimers did so very weakly, outcomes that may reflect the completeness of their glycan shields. The AMC011 trimer induced antibodies that occasionally cross-neutralized heterologous tier 2 viruses, sometimes at high titer. Cross-neutralizing antibodies were more frequently elicited by a trivalent combination of AMC008, AMC009, and AMC011 trimers, all derived from subtype B viruses. Each of these three individual trimers could deplete the NAb activity from the rabbit sera. Mapping the polyclonal sera by electron microscopy revealed that antibodies of multiple specificities could bind to sites on both autologous and heterologous trimers. These results advance our understanding of how to use Env trimers in multivalent vaccination regimens and the immunogenicity of trimers derived from elite neutralizers. IMPORTANCE Elite neutralizers, i.e., individuals who developed unusually broad and potent neutralizing antibody responses, might serve as blueprints for HIV-1 vaccine design. Here, we studied the immunogenicity of native-like recombinant envelope glycoprotein (Env) trimers based on viral sequences from elite neutralizers. While immunization with single trimers from elite neutralization did not recapitulate the breadth and potency of neutralization observed in these infected individuals, a combination of three subtype B Env trimers from elite neutralizers resulted in some neutralization breadth within subtype B viruses. These results should guide future efforts to design vaccines to induce broadly neutralizing antibodies.

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