Head-to-Head Comparison of Poxvirus NYVAC and ALVAC Vectors Expressing Identical HIV-1 Clade C Immunogens in Prime-Boost Combination with Env Protein in Nonhuman Primates

ABSTRACTWe compared the HIV-1-specific cellular and humoral immune responses elicited in rhesus macaques immunized with two poxvirus vectors (NYVAC and ALVAC) expressing the same HIV-1 antigens from clade C, Env gp140 as a trimeric cell-released protein and a Gag-Pol-Nef polyprotein as Gag-induced virus-like particles (VLPs) (referred to as NYVAC-C and ALVAC-C). The immunization protocol consisted of two doses of the corresponding poxvirus vector plus two doses of a combination of the poxvirus vector and a purified HIV-1 gp120 protein from clade C. This immunogenicity profile was also compared to that elicited by vaccine regimens consisting of two doses of the ALVAC vector expressing HIV-1 antigens from clades B/E (ALVAC-vCP1521) plus two doses of a combination of ALVAC-vCP1521 and HIV-1 gp120 protein from clades B/E (similar to the RV144 trial regimen) or clade C. The results showed that immunization of macaques with NYVAC-C stimulated at different times more potent HIV-1-specific CD4+T-cell responses and induced a trend toward higher-magnitude HIV-1-specific CD8+T-cell immune responses than did ALVAC-C. Furthermore, NYVAC-C induced a trend toward higher levels of binding IgG antibodies against clade C HIV-1 gp140, gp120, or murine leukemia virus (MuLV) gp70-scaffolded V1/V2 and toward best cross-clade-binding IgG responses against HIV-1 gp140 from clades A, B, and group M consensus, than did ALVAC-C. Of the linear binding IgG responses, most were directed against the V3 loop in all immunization groups. Additionally, NYVAC-C and ALVAC-C also induced similar levels of HIV-1-neutralizing antibodies and antibody-dependent cellular cytotoxicity (ADCC) responses. Interestingly, binding IgA antibody levels against HIV-1 gp120 or MuLV gp70-scaffolded V1/V2 were absent or very low in all immunization groups. Overall, these results provide a comprehensive survey of the immunogenicity of NYVAC versus ALVAC expressing HIV-1 antigens in nonhuman primates and indicate that NYVAC may represent an alternative candidate to ALVAC in the development of a future HIV-1 vaccine.IMPORTANCEThe finding of a safe and effective HIV/AIDS vaccine immunogen is one of the main research priorities. Here, we generated two poxvirus-based HIV vaccine candidates (NYVAC and ALVAC vectors) expressing the same clade C HIV-1 antigens in separate vectors, and we analyzed in nonhuman primates their immunogenicity profiles. The results showed that immunization with NYVAC-C induced a trend toward higher HIV-1-specific cellular and humoral immune responses than did ALVAC-C, indicating that this new NYVAC vector could be a novel optimized HIV/AIDS vaccine candidate for human clinical trials.

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HIV/AIDS Vaccine Candidates Based on Replication-Competent Recombinant Poxvirus NYVAC-C-KC Expressing Trimeric gp140 and Gag-Derived Virus-Like Particles or Lacking the Viral Molecule B19 That Inhibits Type I Interferon Activate Relevant HIV-1-Specific B and T Cell Immune Functions in Nonhuman Primates

Journal of Virology ◽

10.1128/jvi.02182-16 ◽

2017 ◽

Vol 91 (9) ◽

Cited By ~ 16

Author(s):

Juan García-Arriaza ◽

Beatriz Perdiguero ◽

Jonathan L. Heeney ◽

Michael S. Seaman ◽

David C. Montefiori ◽

...

Keyword(s):

T Cell ◽

Nonhuman Primates ◽

Type I Interferon ◽

Interferon Response ◽

Type I ◽

Vaccine Candidates ◽

Aids Vaccine ◽

Clade C ◽

Hiv 1 ◽

Hiv Aids

ABSTRACT The nonreplicating attenuated poxvirus vector NYVAC expressing clade C(CN54) HIV-1 Env(gp120) and Gag-Pol-Nef antigens (NYVAC-C) showed limited immunogenicity in phase I clinical trials. To enhance the capacity of the NYVAC vector to trigger broad humoral responses and a more balanced activation of CD4+ and CD8+ T cells, here we compared the HIV-1-specific immunogenicity elicited in nonhuman primates immunized with two replicating NYVAC vectors that have been modified by the insertion of the K1L and C7L vaccinia virus host range genes and express the clade C(ZM96) trimeric HIV-1 gp140 protein or a Gag(ZM96)-Pol-Nef(CN54) polyprotein as Gag-derived virus-like particles (termed NYVAC-C-KC). Additionally, one NYVAC-C-KC vector was generated by deleting the viral gene B19R, an inhibitor of the type I interferon response (NYVAC-C-KC-ΔB19R). An immunization protocol mimicking that of the RV144 phase III clinical trial was used. Two groups of macaques received two doses of the corresponding NYVAC-C-KC vectors (weeks 0 and 4) and booster doses with NYVAC-C-KC vectors plus the clade C HIV-1 gp120 protein (weeks 12 and 24). The two replicating NYVAC-C-KC vectors induced enhanced and similar HIV-1-specific CD4+ and CD8+ T cell responses, similar levels of binding IgG antibodies, low levels of IgA antibodies, and high levels of antibody-dependent cellular cytotoxicity responses and HIV-1-neutralizing antibodies. Small differences within the NYVAC-C-KC-ΔB19R group were seen in the magnitude of CD4+ and CD8+ T cells, the induction of some cytokines, and the neutralization of some HIV-1 isolates. Thus, replication-competent NYVAC-C-KC vectors acquired relevant immunological properties as vaccine candidates against HIV/AIDS, and the viral B19 molecule exerts some control of immune functions. IMPORTANCE It is of special importance to find a safe and effective HIV/AIDS vaccine that can induce strong and broad T cell and humoral immune responses correlating with HIV-1 protection. Here we developed novel replicating poxvirus NYVAC-based HIV/AIDS vaccine candidates expressing clade C HIV-1 antigens, with one of them lacking the vaccinia virus B19 protein, an inhibitor of the type I interferon response. Immunization of nonhuman primates with these novel NYVAC-C-KC vectors and the protein component gp120 elicited high levels of T cell and humoral immune responses, with the vector containing a deletion in B19R inducing a trend toward a higher magnitude of CD4+ and CD8+ T cell responses and neutralization of some HIV-1 strains. These poxvirus vectors could be considered HIV/AIDS vaccine candidates based on their activation of potential immune correlates of protection.

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Immune correlates of the Thai RV144 HIV vaccine regimen in South Africa

Science Translational Medicine ◽

10.1126/scitranslmed.aax1880 ◽

2019 ◽

Vol 11 (510) ◽

pp. eaax1880 ◽

Cited By ~ 10

Author(s):

Glenda E. Gray ◽

Ying Huang ◽

Nicole Grunenberg ◽

Fatima Laher ◽

Surita Roux ◽

...

Keyword(s):

South Africa ◽

T Cell ◽

Immune Responses ◽

Hiv Vaccine ◽

Antibody Responses ◽

Vaccine Regimen ◽

Humoral Immune ◽

Immune Correlates ◽

Clade C ◽

Hiv 1

One of the most successful HIV vaccines to date, the RV144 vaccine tested in Thailand, demonstrated correlates of protection including cross-clade V1V2 immunoglobulin G (IgG) breadth, Env-specific CD4+ T cell polyfunctionality, and antibody-dependent cellular cytotoxicity (ADCC) in vaccinees with low IgA binding. The HIV Vaccine Trials Network (HVTN) 097 trial evaluated this vaccine regimen in South Africa, where clade C HIV-1 predominates. We compared cellular and humoral responses at peak and durability immunogenicity time points in HVTN 097 and RV144 vaccinee samples, and evaluated vaccine-matched and cross-clade immune responses. At peak immunogenicity, HVTN 097 vaccinees exhibited significantly higher cellular and humoral immune responses than RV144 vaccinees. CD4+ T cell responses were more frequent in HVTN 097 irrespective of age and sex, and CD4+ T cell Env-specific functionality scores were higher in HVTN 097. Env-specific CD40L+ CD4+ T cells were more common in HVTN 097, with individuals having this pattern of expression demonstrating higher median antibody responses to HIV-1 Env. IgG and IgG3 binding antibody rates and response magnitude to gp120 vaccine– and V1V2 vaccine–matched antigens were higher or comparable in HVTN 097 than in RV144 ADCC, and ADCP functional antibody responses were elicited in HVTN 097. Env-specific IgG and CD4+ Env responses declined significantly over time in both trials. Overall, cross-clade immune responses associated with protection were better than expected in South Africa, suggesting wider applicability of this regimen.

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Peptide immunogens based on the envelope region of HIV-1 are recognized by HIV/AIDS patient polyclonal antibodies and induce strong humoral immune responses in mice and rabbits

Molecular Immunology ◽

10.1016/s0161-5890(03)00163-9 ◽

2003 ◽

Vol 40 (6) ◽

pp. 327-335 ◽

Cited By ~ 12

Author(s):

R Hewer

Keyword(s):

Immune Responses ◽

Polyclonal Antibodies ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Hiv 1 ◽

Hiv Aids

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Glycopeptide epitope facilitates HIV-1 envelope specific humoral immune responses by eliciting T cell help

Nature Communications ◽

10.1038/s41467-020-16319-0 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 2

Author(s):

Lina Sun ◽

Amy V. Paschall ◽

Dustin R. Middleton ◽

Mayumi Ishihara ◽

Ahmet Ozdilek ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Humoral Immune ◽

Humoral Immune Responses ◽

T Cell Help ◽

Hiv 1

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Humoral immune responses by prime-boost heterologous route immunizations with CTB-MPR649–684, a mucosal subunit HIV/AIDS vaccine candidate

Vaccine ◽

10.1016/j.vaccine.2006.03.045 ◽

2006 ◽

Vol 24 (23) ◽

pp. 5047-5055 ◽

Cited By ~ 41

Author(s):

Nobuyuki Matoba ◽

Brian C. Geyer ◽

Jacquelyn Kilbourne ◽

Annette Alfsen ◽

Morgane Bomsel ◽

...

Keyword(s):

Immune Responses ◽

Vaccine Candidate ◽

Humoral Immune ◽

Aids Vaccine ◽

Humoral Immune Responses ◽

Hiv Aids

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Scarcity or Absence of Humoral Immune Responses in the Plasma and Cervicovaginal Lavage Fluids of Heavily HIV-1-Exposed But Persistently Seronegative Women

AIDS Research and Human Retroviruses ◽

10.1089/aid.2010.0169 ◽

2011 ◽

Vol 27 (5) ◽

pp. 469-486 ◽

Cited By ~ 35

Author(s):

Jiri Mestecky ◽

Peter F. Wright ◽

Lucia Lopalco ◽

Herman F. Staats ◽

Pamela A. Kozlowski ◽

...

Keyword(s):

Immune Responses ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Cervicovaginal Lavage ◽

Hiv 1

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Over‐expression of p190Rho GEF enhances B‐cell activation and germinal center formation in T‐cell‐dependent humoral immune responses

Immunology and Cell Biology ◽

10.1111/imcb.12286 ◽

2019 ◽

Vol 97 (10) ◽

pp. 877-887 ◽

Cited By ~ 1

Author(s):

Ji Hye Jeong ◽

Yun Jung Ha ◽

So‐Yeon Choi ◽

Jee‐Hae Kim ◽

Yungdae Yun ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

B Cell ◽

Germinal Center ◽

Cell Activation ◽

B Cell Activation ◽

Over Expression ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Germinal Center Formation

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A Glycoconjugate Antigen Based on the Recognition Motif of a Broadly Neutralizing Human Immunodeficiency Virus Antibody, 2G12, Is Immunogenic but Elicits Antibodies Unable To Bind to the Self Glycans of gp120

Journal of Virology ◽

10.1128/jvi.00293-08 ◽

2008 ◽

Vol 82 (13) ◽

pp. 6359-6368 ◽

Cited By ~ 85

Author(s):

Rena D. Astronomo ◽

Hing-Ken Lee ◽

Christopher N. Scanlan ◽

Ralph Pantophlet ◽

Cheng-Yuan Huang ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Neutralizing Antibody ◽

Humoral Immune ◽

Aids Vaccine ◽

Humoral Immune Responses ◽

Copy Numbers ◽

Immunodeficiency Virus ◽

Broadly Neutralizing Antibody ◽

Hiv 1

ABSTRACT The glycan shield of human immunodeficiency virus type 1 (HIV-1) gp120 contributes to viral evasion from humoral immune responses. However, the shield is recognized by the HIV-1 broadly neutralizing antibody (Ab), 2G12, at a relatively conserved cluster of oligomannose glycans. The discovery of 2G12 raises the possibility that a carbohydrate immunogen may be developed that could elicit 2G12-like neutralizing Abs and contribute to an AIDS vaccine. We have previously dissected the fine specificity of 2G12 and reported that the synthetic tetramannoside (Man4) that corresponds to the D1 arm of Man9GlcNAc2 inhibits 2G12 binding to gp120 as efficiently as Man9GlcNAc2 itself, indicating the potential use of Man4 as a building block for creating immunogens. Here, we describe the development of neoglycoconjugates displaying variable copy numbers of Man4 on bovine serum albumin (BSA) molecules by conjugation to Lys residues. The increased valency enhances the apparent affinity of 2G12 for Man4 up to a limit which is achieved at ∼10 copies per BSA molecule, beyond which no further enhancement is observed. Immunization of rabbits with BSA-(Man4)14 elicits significant serum Ab titers to Man4. However, these Abs are unable to bind gp120. Further analysis reveals that the elicited Abs bind a variety of unbranched and, to a lesser extent, branched Man9 derivatives but not natural N-linked oligomannose containing the chitobiose core. These results suggest that Abs can be readily elicited against the D1 arm; however, potential differences in the presentation of Man4 on neoglycoconjugates, compared to glycoproteins, poses challenges for eliciting anti-mannose Abs capable of cross-reacting with gp120 and HIV-1.

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