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

2019 ◽  
Vol 11 (510) ◽  
pp. eaax1880 ◽  
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.

scholarly journals 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

2015 ◽  
Vol 89 (16) ◽  
pp. 8525-8539 ◽  
Author(s):  
Juan García-Arriaza ◽  
Beatriz Perdiguero ◽  
Jonathan Heeney ◽  
Michael Seaman ◽  
David C. Montefiori ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Nonhuman Primates ◽  
Humoral Immune ◽  
Aids Vaccine ◽  
Humoral Immune Responses ◽  
Gp120 Protein ◽  
Clade C ◽  
Hiv 1 ◽  
Hiv Aids

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.

scholarly journals Development of a 3Mut-Apex-Stabilized Envelope Trimer That Expands HIV-1 Neutralization Breadth When Used To Boost Fusion Peptide-Directed Vaccine-Elicited Responses

2020 ◽  
Vol 94 (13) ◽  
Author(s):  
Gwo-Yu Chuang ◽  
Yen-Ting Lai ◽  
Jeffrey C. Boyington ◽  
Cheng Cheng ◽  
Hui Geng ◽  
...  
Keyword(s):  
Immune Responses ◽  
Crystal Structures ◽  
Guinea Pigs ◽  
Fusion Peptide ◽  
Dihedral Angles ◽  
Vaccine Regimen ◽  
Closed Conformation ◽  
Clade C ◽  
Humoral Responses ◽  
Hiv 1

ABSTRACT HIV-1 envelope (Env) trimers, stabilized in a prefusion-closed conformation, can elicit humoral responses capable of neutralizing HIV-1 strains closely matched in sequence to the immunizing strain. One strategy to increase elicited neutralization breadth involves vaccine priming of immune responses against a target site of vulnerability, followed by vaccine boosting of these responses with prefusion-closed Env trimers. This strategy has succeeded at the fusion peptide (FP) site of vulnerability in eliciting cross-clade neutralizing responses in standard vaccine-test animals. However, the breadth and potency of the elicited responses have been less than optimal. Here, we identify three mutations (3mut), Met302, Leu320, and Pro329, that stabilize the apex of the Env trimer in a prefusion-closed conformation and show antigenically, structurally, and immunogenically that combining 3mut with other approaches (e.g., repair and stabilize and glycine-helix breaking) yields well-behaved clade C-Env trimers capable of boosting the breadth of FP-directed responses. Crystal structures of these trimers confirmed prefusion-closed apexes stabilized by hydrophobic patches contributed by Met302 and Leu320, with Pro329 assuming canonically restricted dihedral angles. We substituted the N-terminal eight residues of FP (FP8, residues 512 to 519) of these trimers with the second most prevalent FP8 sequence (FP8v2, AVGLGAVF) and observed a 3mut-stabilized consensus clade C-Env trimer with FP8v2 to boost the breadth elicited in guinea pigs of FP-directed responses induced by immunogens containing the most prevalent FP8 sequence (FP8v1, AVGIGAVF). Overall, 3mut can stabilize the Env trimer apex, and the resultant apex-stabilized Env trimers can be used to expand the neutralization breadth elicited against the FP site of vulnerability. IMPORTANCE A major hurdle to the development of an effective HIV-1 vaccine is the elicitation of serum responses capable of neutralizing circulating strains of HIV, which are extraordinarily diverse in sequence and often highly neutralization resistant. Recently, we showed how sera with 20 to 30% neutralization breadth could, nevertheless, be elicited in standard vaccine test animals by priming with the most prevalent N-terminal 8 residues of the HIV-1 fusion peptide (FP8), followed by boosting with a stabilized BG505-envelope (Env) trimer. Here, we show that subsequent boosting with a 3mut-apex-stabilized consensus C-Env trimer, modified to have the second most prevalent FP8 sequence, elicits higher neutralization breadth than that induced by continued boosting with the stabilized BG505-Env trimer. With increased neutralizing breadth elicited by boosting with a heterologous trimer containing the second most prevalent FP8 sequence, the fusion peptide-directed immune-focusing approach moves a step closer toward realizing an effective HIV-1 vaccine regimen.

scholarly journals Rectal Microbiome Composition Correlates with Humoral Immunity to HIV-1 in Vaccinated Rhesus Macaques

mSphere ◽  
2019 ◽  
Vol 4 (6) ◽  
Author(s):  
Sonny R. Elizaldi ◽  
Anil Verma ◽  
Korey A. Walter ◽  
Matthew Rolston ◽  
Ashok R. Dinasarapu ◽  
...  
Keyword(s):  
Immune Responses ◽  
Rhesus Macaques ◽  
Temporal Stability ◽  
Hiv Vaccine ◽  
Antibody Responses ◽  
Critical Determinant ◽  
Dynamic Component ◽  
Microbiome Composition ◽  
Vaccine Immunogenicity ◽  
Hiv 1

ABSTRACT The microbiome is an integral and dynamic component of the host and is emerging as a critical determinant of immune responses; however, its influence on vaccine immunogenicity is largely not well understood. Here, we examined the pivotal relationship between the mucosal microbiome and vaccine-induced immune responses by assessing longitudinal changes in vaginal and rectal microbiome profiles after intradermal immunization with a human immunodeficiency virus type 1 (HIV-1) DNA vaccine in adult rhesus macaques that received two prior DNA primes. We report that both vaginal and rectal microbiomes were dominated by Firmicutes but were composed of distinct genera, denoting microbiome specialization across mucosal tissues. Following immunization, the vaginal microbiome was resilient, except for a transient decrease in Streptococcus. In contrast, the rectal microbiome was far more responsive to vaccination, exhibiting an increase in the ratio of Firmicutes to Bacteroidetes. Within Bacteroidetes, multiple genera were significantly decreased, including Prevotella, Alloprevotella, Bacteroides, Acetobacteroides, Falsiporphyromonas, and Anaerocella. Decreased abundance of Prevotella correlated with induction of gut-homing α4β7+ effector CD4 T cells. Prevotella abundance also negatively correlated with rectal HIV-1 specific IgG levels. While rectal Lactobacillus was unaltered following DNA vaccination, baseline Lactobacillus abundance showed strong associations with higher rectal HIV-1 gp140 IgA induced following a protein boost. Similarly, the abundance of Clostridium in cluster IV was associated with higher rectal HIV-1 gp140 IgG responses. Collectively, these data reveal that the temporal stability of bacterial communities following DNA immunization is site dependent and highlight the importance of host-microbiome interactions in shaping HIV-1 vaccine responses. Our findings have significant implications for microbial manipulation as a strategy to enhance HIV vaccine-induced mucosal immunity. IMPORTANCE There is considerable effort directed toward evaluating HIV-1 vaccine platforms to select the most promising candidates for enhancing mucosal HIV-1 antibody. The most successful thus far, the RV144 trial provided partial protection due to waning HIV-1 antibody titers. In order to develop an effective HIV vaccine, it may therefore be important to understand how biological factors, such as the microbiome, modulate host immune responses. Furthermore, as intestinal microbiota antigens may generate antibodies cross-reactive to the HIV-1 envelope glycoprotein, understanding the relationship between gut microbiota composition and HIV-1 envelope antibody responses after vaccination is important. Here, we demonstrate for the first time in rhesus macaques that the rectal microbiome composition can influence HIV-1 vaccine immunogenicity, and we report temporal changes in the mucosal microbiome profile following HIV-1 vaccination. Our results could inform findings from the HIV Vaccine Trials Network (HVTN) vaccine studies and contribute to an understanding of how the microbiome influences HIV-1 antibody responses.

scholarly journals Potential To Streamline Heterologous DNA Prime and NYVAC/Protein Boost HIV Vaccine Regimens in Rhesus Macaques by Employing Improved Antigens

2016 ◽  
Vol 90 (8) ◽  
pp. 4133-4149 ◽  
Author(s):  
Benedikt Asbach ◽  
Alexander Kliche ◽  
Josef Köstler ◽  
Beatriz Perdiguero ◽  
Mariano Esteban ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cell ◽  
Immune Responses ◽  
Rhesus Macaques ◽  
T Cell Responses ◽  
Hiv Vaccine ◽  
The Novel ◽  
Cell Responses ◽  
Protein Boost ◽  
Clade C

ABSTRACTIn a follow-up to the modest efficacy observed in the RV144 trial, researchers in the HIV vaccine field seek to substantiate and extend the results by evaluating other poxvirus vectors and combinations with DNA and protein vaccines. Earlier clinical trials (EuroVacc trials 01 to 03) evaluated the immunogenicity of HIV-1 clade C GagPolNef and gp120 antigens delivered via the poxviral vector NYVAC. These showed that a vaccination regimen including DNA-C priming prior to a NYVAC-C boost considerably enhanced vaccine-elicited immune responses compared to those with NYVAC-C alone. Moreover, responses were improved by using three as opposed to two DNA-C primes. In the present study, we assessed in nonhuman primates whether such vaccination regimens can be streamlined further by using fewer and accelerated immunizations and employing a novel generation of improved DNA-C and NYVAC-C vaccine candidates designed for higher expression levels and more balanced immune responses. Three different DNA-C prime/NYVAC-C+ protein boost vaccination regimens were tested in rhesus macaques. All regimens elicited vigorous and well-balanced CD8+and CD4+T cell responses that were broad and polyfunctional. Very high IgG binding titers, substantial antibody-dependent cellular cytotoxicity (ADCC), and modest antibody-dependent cell-mediated virus inhibition (ADCVI), but very low neutralization activity, were measured after the final immunizations. Overall, immune responses elicited in all three groups were very similar and of greater magnitude, breadth, and quality than those of earlier EuroVacc vaccines. In conclusion, these findings indicate that vaccination schemes can be simplified by using improved antigens and regimens. This may offer a more practical and affordable means to elicit potentially protective immune responses upon vaccination, especially in resource-constrained settings.IMPORTANCEWithin the EuroVacc clinical trials, we previously assessed the immunogenicity of HIV clade C antigens delivered in a DNA prime/NYVAC boost regimen. The trials showed that the DNA prime crucially improved the responses, and three DNA primes with a NYVAC boost appeared to be optimal. Nevertheless, T cell responses were primarily directed toward Env, and humoral responses were modest. The aim of this study was to assess improved antigens for the capacity to elicit more potent and balanced responses in rhesus macaques, even with various simpler immunization regimens. Our results showed that the novel antigens in fact elicited larger numbers of T cells with a polyfunctional profile and a good Env-GagPolNef balance, as well as high-titer and Fc-functional antibody responses. Finally, comparison of the different schedules indicates that a simpler regimen of only two DNA primes and one NYVAC boost in combination with protein may be very efficient, thus showing that the novel antigens allow for easier immunization protocols.

scholarly journals Antigen targeting to dendritic cells elicits long-lived T cell help for antibody responses

2006 ◽  
Vol 203 (3) ◽  
pp. 599-606 ◽  
Author(s):  
Silvia B. Boscardin ◽  
Julius C.R. Hafalla ◽  
Revati F. Masilamani ◽  
Alice O. Kamphorst ◽  
Henry A. Zebroski ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Immune Responses ◽  
Lymphoid Organs ◽  
Antibody Responses ◽  
Carrier Protein ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Maturation Stimulus ◽  
T Cell Help

Resistance to several prevalent infectious diseases requires both cellular and humoral immune responses. T cell immunity is initiated by mature dendritic cells (DCs) in lymphoid organs, whereas humoral responses to most antigens require further collaboration between primed, antigen-specific helper T cells and naive or memory B cells. To determine whether antigens delivered to DCs in lymphoid organs induce T cell help for antibody responses, we targeted a carrier protein, ovalbumin (OVA), to DCs in the presence of a maturation stimulus and assayed for antibodies to a hapten, (4-hydroxy-3-nitrophenyl) acetyl (NP), after boosting with OVA-NP. A single DC-targeted immunization elicited long-lived T cell helper responses to the carrier protein, leading to large numbers of antibody-secreting cells and high titers of high-affinity antihapten immunoglobulin Gs. Small doses of DC-targeted OVA induced higher titers and a broader spectrum of anti-NP antibody isotypes than large doses of OVA in alum adjuvant. Similar results were obtained when the circumsporozoite protein of Plasmodium yoelii was delivered to DCs. We conclude that antigen targeting to DCs combined with a maturation stimulus produces broad-based and long-lived T cell help for humoral immune responses.

scholarly journals Durable Humoral and Cellular Immune Responses Following Ad26.COV2.S Vaccination for COVID-19

2021 ◽  
Author(s):  
Dan H. Barouch ◽  
Kathryn Stephenson ◽  
Jerald Sadoff ◽  
Jingyou Yu ◽  
Aiquan Chang ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Single Shot ◽  
Efficacy Data ◽  
Vaccine Regimen ◽  
Cell Responses ◽  
Cellular Immune Responses ◽  
Cellular Immune

Interim immunogenicity and efficacy data for the Ad26.COV2.S vaccine for COVID-19 have recently been reported. We describe here the 8-month durability of humoral and cellular immune responses in 20 individuals who received one or two doses of 5x10^10 vp or 10^11 vp Ad26.COV2.S and in 5 participants who received placebo. We evaluated antibody and T cell responses on day 239, which was 8 months after the single-shot vaccine regimen (N=10) or 6 months after the two-shot vaccine regimen (N=10), although the present study was not powered to compare these regimens. We also report neutralizing antibody responses against the parental SARS-CoV-2 WA1/2020 strain as well as against the SARS-CoV-2 variants D614G, B.1.1.7 (alpha), B.1.617.1 (kappa), B.1.617.2 (delta), P.1 (gamma), B.1.429 (epsilon), and B.1.351 (beta).

scholarly journals Virological and Immunological Characterization of Novel NYVAC-Based HIV/AIDS Vaccine Candidates Expressing Clade C Trimeric Soluble gp140(ZM96) and Gag(ZM96)-Pol-Nef(CN54) as Virus-Like Particles

2014 ◽  
Vol 89 (2) ◽  
pp. 970-988 ◽  
Author(s):  
Beatriz Perdiguero ◽  
Carmen Elena Gómez ◽  
Victoria Cepeda ◽  
Lucas Sánchez-Sampedro ◽  
Juan García-Arriaza ◽  
...  
Keyword(s):  
Immune Responses ◽  
Human Cells ◽  
Hiv Vaccine ◽  
Phase Iii ◽  
Newborn Mice ◽  
Vaccine Candidates ◽  
Virus Like Particles ◽  
Clade C ◽  
Hiv 1 ◽  
Hiv Aids

ABSTRACTThe generation of vaccines against HIV/AIDS able to induce long-lasting protective immunity remains a major goal in the HIV field. The modest efficacy (31.2%) against HIV infection observed in the RV144 phase III clinical trial highlighted the need for further improvement of HIV vaccine candidates, formulation, and vaccine regimen. In this study, we have generated two novel NYVAC vectors, expressing HIV-1 clade C gp140(ZM96) (NYVAC-gp140) or Gag(ZM96)-Pol-Nef(CN54) (NYVAC-Gag-Pol-Nef), and defined their virological and immunological characteristics in cultured cells and in mice. The insertion of HIV genes does not affect the replication capacity of NYVAC recombinants in primary chicken embryo fibroblast cells, HIV sequences remain stable after multiple passages, and HIV antigens are correctly expressed and released from cells, with Env as a trimer (NYVAC-gp140), while in NYVAC-Gag-Pol-Nef-infected cells Gag-induced virus-like particles (VLPs) are abundant. Electron microscopy revealed that VLPs accumulated with time at the cell surface, with no interference with NYVAC morphogenesis. Both vectors trigger specific innate responses in human cells and show an attenuation profile in immunocompromised adult BALB/c and newborn CD1 mice after intracranial inoculation. Analysis of the immune responses elicited in mice after homologous NYVAC prime/NYVAC boost immunization shows that recombinant viruses induced polyfunctional Env-specific CD4 or Gag-specific CD8 T cell responses. Antibody responses against gp140 and p17/p24 were elicited. Our findings showed important insights into virus-host cell interactions of NYVAC vectors expressing HIV antigens, with the activation of specific immune parameters which will help to unravel potential correlates of protection against HIV in human clinical trials with these vectors.IMPORTANCEWe have generated two novel NYVAC-based HIV vaccine candidates expressing HIV-1 clade C trimeric soluble gp140 (ZM96) and Gag(ZM96)-Pol-Nef(CN54) as VLPs. These vectors are stable and express high levels of both HIV-1 antigens. Gag-induced VLPs do not interfere with NYVAC morphogenesis, are highly attenuated in immunocompromised and newborn mice after intracranial inoculation, trigger specific innate immune responses in human cells, and activate T (Env-specific CD4 and Gag-specific CD8) and B cell immune responses to the HIV antigens, leading to high antibody titers against gp140. For these reasons, these vectors can be considered vaccine candidates against HIV/AIDS and currently are being tested in macaques and humans.

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

2020 ◽  
Vol 11 (1) ◽  
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

scholarly journals Dose Effects of Recombinant Adenovirus Immunization in Rodents

Vaccines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 144 ◽  
Author(s):  
Eric A. Weaver
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Recombinant Adenovirus ◽  
T Cell Responses ◽  
Antibody Responses ◽  
Vaccine Platform ◽  
Cell Responses ◽  
Immune Correlates ◽  
Cell Immunity ◽  
Dose Dependent

Recombinant adenovirus type 5 (rAd) has been used as a vaccine platform against many infectious diseases and has been shown to be an effective vaccine vector. The dose of the vaccine varies significantly from study to study, making it very difficult to compare immune responses and vaccine efficacy. This study determined the immune correlates induced by serial dilutions of rAd vaccines delivered intramuscularly (IM) and intranasally (IN) to mice and rats. When immunized IM, mice had substantially higher antibody responses at the higher vaccine doses, whereas, the IN immunized mice showed a lower response to the higher rAd vaccine doses. Rats did not show dose-dependent antibody responses to increasing vaccine doses. The IM immunized mice and rats also showed significant dose-dependent T cell responses to the rAd vaccine. However, the T cell immunity plateaued in both mice and rats at 109 and 1010 vp/animal, respectively. Additionally, the highest dose of vaccine in mice and rats did not improve the T cell responses. A final vaccine analysis using a lethal influenza virus challenge showed that despite the differences in the immune responses observed in the mice, the mice had very similar patterns of protection. This indicates that rAd vaccines induced dose-dependent immune responses, especially in IM immunized animals, and that immune correlates are not as predictive of protection as initially thought.

scholarly journals HIV-1 gp120 and Modified Vaccinia Virus Ankara (MVA) gp140 Boost Immunogens Increase Immunogenicity of a DNA/MVA HIV-1 Vaccine

2017 ◽  
Vol 91 (24) ◽  
Author(s):  
Xiaoying Shen ◽  
Rahul Basu ◽  
Sheetal Sawant ◽  
David Beaumont ◽  
Sue Fen Kwa ◽  
...  
Keyword(s):  
T Cell ◽  
Vaccinia Virus ◽  
T Cell Responses ◽  
Hiv Vaccine ◽  
Antibody Responses ◽  
Cell Responses ◽  
Modified Vaccinia Virus Ankara ◽  
Gp120 Protein ◽  
Boost Vaccine ◽  
Hiv 1

ABSTRACT An important goal of human immunodeficiency virus (HIV) vaccine design is identification of strategies that elicit effective antiviral humoral immunity. One novel approach comprises priming with DNA and boosting with modified vaccinia virus Ankara (MVA) expressing HIV-1 Env on virus-like particles. In this study, we evaluated whether the addition of a gp120 protein in alum or MVA-expressed secreted gp140 (MVAgp140) could improve immunogenicity of a DNA prime-MVA boost vaccine. Five rhesus macaques per group received two DNA primes at weeks 0 and 8 followed by three MVA boosts (with or without additional protein or MVAgp140) at weeks 18, 26, and 40. Both boost immunogens enhanced the breadth of HIV-1 gp120 and V1V2 responses, antibody-dependent cellular cytotoxicity (ADCC), and low-titer tier 1B and tier 2 neutralizing antibody responses. However, there were differences in antibody kinetics, linear epitope specificity, and CD4 T cell responses between the groups. The gp120 protein boost elicited earlier and higher peak responses, whereas the MVAgp140 boost resulted in improved antibody durability and comparable peak responses after the final immunization. Linear V3 specific IgG responses were particularly enhanced by the gp120 boost, whereas the MVAgp140 boost also enhanced responses to linear C5 and C2.2 epitopes. Interestingly, gp120, but not the MVAgp140 boost, increased peak CD4+ T cell responses. Thus, both gp120 and MVAgp140 can augment potential protection of a DNA/MVA vaccine by enhancing gp120 and V1/V2 antibody responses, whereas potential protection by gp120, but not MVAgp140 boosts, may be further impacted by increased CD4+ T cell responses. IMPORTANCE Prior immune correlate analyses with humans and nonhuman primates revealed the importance of antibody responses in preventing HIV-1 infection. A DNA prime-modified vaccinia virus Ankara (MVA) boost vaccine has proven to be potent in eliciting antibody responses. Here we explore the ability of boosts with recombinant gp120 protein or MVA-expressed gp140 to enhance antibody responses elicited by the GOVX-B11 DNA prime-MVA boost vaccine. We found that both types of immunogen boosts enhanced potentially protective antibody responses, whereas the gp120 protein boosts also increased CD4+ T cell responses. Our data provide important information for HIV vaccine designs that aim for effective and balanced humoral and T cell responses.

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