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Journal of Virology Oct 2021Recombinant viral vectors represent an important platform for vaccine delivery. Our recent studies have demonstrated distinct innate immune profiles in responding to...
Recombinant viral vectors represent an important platform for vaccine delivery. Our recent studies have demonstrated distinct innate immune profiles in responding to viral vectors of different families (e.g., adenovirus versus poxvirus): while human Ad5 vector is minimally innate immune stimulatory, the poxviral vector ALVAC induces strong innate response and stimulates type I interferon (IFN) and inflammasome activation. However, the impact of the innate immune signaling on vaccine-induced adaptive immunity in viral vector vaccination is less clear. Here, we show that Modified Vaccinia Ankara (MVA), another poxviral vector, stimulated a type I IFN response in innate immune cells through cGAS-STING. Using MVA-HIV vaccine as a model, we found that type I IFN signaling promoted the generation of humoral immunity in MVA-HIV vaccination . Following vaccination, type I IFN receptor-knockout (IFNAR1) mice produced significantly lower levels of total and HIV gp120-specific antibodies compared to wild-type (WT) mice. Consistent with the antibody response, a type I IFN signaling deficiency also led to reduced levels of plasma cells and memory-like B cells compared to WT mice. Furthermore, analysis of vaccine-induced CD4 T cells showed that type I IFN signaling also promoted the generation of a vaccine-specific CD4 T-cell response and a T follicular helper (Tfh) response in mice. Together, our data indicate a role for type I IFN signaling in promoting humoral immunity in poxviral vector vaccination. The study suggests that modulating type I IFN and its associated innate immune pathways will likely affect vaccine efficacy. Viral vectors, including MVA, are an important antigen delivery platform and have been commonly used in vaccine development. Understanding the innate host-viral vector interactions and their impact on vaccine-induced immunity is critical but understudied. Using MVA-HIV vaccination of WT and IFNAR1 mice as a model, we report that type I IFN signaling promotes humoral immunity in MVA vaccination, including vaccine-induced antibody, B-cell, and Tfh responses. Our findings provide insights that not only add to our basic understanding of host-viral vector interactions but also will aid in improving vaccine design by potentially modulating type I IFN and its associated innate immune pathways in viral vector vaccination.
Topics: AIDS Vaccines; Animals; Genetic Vectors; Humans; Immunity, Humoral; Interferon Type I; Mice; Mice, Inbred C57BL; Mice, Knockout; THP-1 Cells; Vaccine Development; Vaccine Efficacy; Vaccinia virus
PubMed: 34495698
DOI: 10.1128/JVI.00925-21 -
Viruses Mar 2021Over 36 million people worldwide are infected with HIV. Antiretroviral therapy (ART) has proven to be highly effective to prevent HIV-1 transmission, clinical... (Review)
Review
Over 36 million people worldwide are infected with HIV. Antiretroviral therapy (ART) has proven to be highly effective to prevent HIV-1 transmission, clinical progression and death. Despite this success, the number of HIV-1 infected individuals continues increasing and ART should be taken for life. Therefore, there are two main priorities: the development of preventive vaccines to protect from HIV acquisition and achieve an efficient control of HIV infection in the absence of ART (functional cure). In this sense, in the last few years, there has been a broad interest in new and innovative approaches such as mRNA-based vaccines. RNA-based immunogens represent a promising alternative to conventional vaccines because of their high potency, capacity for rapid development and potential for low-cost manufacture and safe administration. Some mRNA-based vaccines platforms against infectious diseases have demonstrated encouraging results in animal models and humans. However, their application is still limited because the instability and inefficient in vivo delivery of mRNA. Immunogens, design, immunogenicity, chemical modifications on the molecule or the vaccine delivery methods are all crucial interventions for improvement. In this review we, will present the current knowledge and challenges in this research field. mRNA vaccines hold great promises as part of a combined strategy, for achieving HIV functional cure.
Topics: AIDS Vaccines; Animals; Cell Line; Drug Delivery Systems; HIV Infections; HIV-1; Humans; Vaccines, Synthetic; mRNA Vaccines
PubMed: 33803790
DOI: 10.3390/v13030501 -
Cell Reports Jul 2023Elicitation of antibodies that neutralize the tier-2 neutralization-resistant isolates that typify HIV-1 transmission has been a long-sought goal. Success with...
Elicitation of antibodies that neutralize the tier-2 neutralization-resistant isolates that typify HIV-1 transmission has been a long-sought goal. Success with prefusion-stabilized envelope trimers eliciting autologous neutralizing antibodies has been reported in multiple vaccine-test species, though not in humans. To investigate elicitation of HIV-1 neutralizing antibodies in humans, here, we analyze B cells from a phase I clinical trial of the "DS-SOSIP"-stabilized envelope trimer from strain BG505, identifying two antibodies, N751-2C06.01 and N751-2C09.01 (named for donor-lineage.clone), that neutralize the autologous tier-2 strain, BG505. Though derived from distinct lineages, these antibodies form a reproducible antibody class that targets the HIV-1 fusion peptide. Both antibodies are highly strain specific, which we attribute to their partial recognition of a BG505-specific glycan hole and to their binding requirements for a few BG505-specific residues. Prefusion-stabilized envelope trimers can thus elicit autologous tier-2 neutralizing antibodies in humans, with initially identified neutralizing antibodies recognizing the fusion-peptide site of vulnerability.
Topics: Humans; AIDS Vaccines; Antibodies, Neutralizing; env Gene Products, Human Immunodeficiency Virus; HIV Antibodies; HIV Infections; HIV Seropositivity; HIV-1; Peptides
PubMed: 37436899
DOI: 10.1016/j.celrep.2023.112755 -
Journal of Virology Sep 2023The envelope (Env) glycoproteins on HIV-1 virions are the sole target of broadly neutralizing antibodies (bNAbs) and the focus of vaccines. However, many cross-reactive...
The envelope (Env) glycoproteins on HIV-1 virions are the sole target of broadly neutralizing antibodies (bNAbs) and the focus of vaccines. However, many cross-reactive conserved epitopes are often occluded on virus particles, contributing to the evasion of humoral immunity. This study aimed to identify the Env epitopes that are exposed/occluded on HIV-1 particles and to investigate the mechanisms contributing to their masking. Using a flow cytometry-based assay, three HIV-1 isolates, and a panel of antibodies, we show that only select epitopes, including V2i, the gp120-g41 interface, and gp41-MPER, are accessible on HIV-1 particles, while V3, V2q, and select CD4bs epitopes are masked. These epitopes become accessible after allosteric conformational changes are induced by the pre-binding of select Abs, prompting us to test if similar conformational changes are required for these Abs to exhibit their neutralization capability. We tested HIV-1 neutralization where the virus-mAb mix was pre-incubated/not pre-incubated for 1 hour prior to adding the target cells. Similar levels of neutralization were observed under both assay conditions, suggesting that the interaction between virus and target cells sensitizes the virions for neutralization via bNAbs. We further show that lectin-glycan interactions can also expose these epitopes. However, this effect is dependent on the lectin specificity. Given that, bNAbs are ideal for providing sterilizing immunity and are the goal of current HIV-1 vaccine efforts, these data offer insight on how HIV-1 may occlude these vulnerable epitopes from the host immune response. In addition, the findings can guide the formulation of effective antibody combinations for therapeutic use. IMPORTANCE The human immunodeficiency virus (HIV-1) envelope (Env) glycoprotein mediates viral entry and is the sole target of neutralizing antibodies. Our data suggest that antibody epitopes including V2q (e.g., PG9, PGT145), CD4bs (e.g., VRC01, 3BNC117), and V3 (2219, 2557) are masked on HIV-1 particles. The PG9 and 2219 epitopes became accessible for binding after conformational unmasking was induced by the pre-binding of select mAbs. Attempts to understand the masking mechanism led to the revelation that interaction between virus and host cells is needed to sensitize the virions for neutralization by broadly neutralizing antibodies (bNAbs). These data provide insight on how bNAbs may gain access to these occluded epitopes to exert their neutralization effects and block HIV-1 infection. These findings have important implications for the way we evaluate the neutralizing efficacy of antibodies and can potentially guide vaccine design.
Topics: Humans; Antibodies, Monoclonal; Broadly Neutralizing Antibodies; HIV Antibodies; HIV Envelope Protein gp120; HIV Infections; HIV-1; Lectins; Epitopes, B-Lymphocyte; Host Microbial Interactions; AIDS Vaccines; Virion; Polysaccharides
PubMed: 37681958
DOI: 10.1128/jvi.00710-23 -
Current Opinion in HIV and AIDS Nov 2023Design of an HIV vaccine that can induce broadly neutralizing antibodies (bnAbs) is a major goal. However, HIV bnAbs are not readily made by the immune system. Rather...
PURPOSE OF REVIEW
Design of an HIV vaccine that can induce broadly neutralizing antibodies (bnAbs) is a major goal. However, HIV bnAbs are not readily made by the immune system. Rather HIV bnAbs are disfavored by a number of virus and host factors. The purpose of the review is to discuss recent progress made in the design and use of immunogens capable of inducing HIV bnAbs in the Duke Consortia for HIV/AIDS Vaccine Development.
RECENT FINDINGS
New immunogens capable of binding with high affinity to unmutated common ancestors (UCAs) of bnAb B cell lineages have been designed and strategies for stabilization of HIV Env in its prefusion state are being developed. Success is starting to be translated from preclinical studies of UCA-targeting immunogens in animals, to success of initiating bnAb lineages in humans.
SUMMARY
Recent progress has been made in both immunogen design and in achieving bnAb B cell lineage induction in animal models and now in human clinical trials. With continued progress, a practical HIV/AIDS vaccine may be possible. However, host constraints on full bnAb maturation remain as potential roadblocks for full maturation of some types of bnAbs.
PubMed: 37751363
DOI: 10.1097/COH.0000000000000820 -
PLoS Pathogens Dec 2020The 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... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
Topics: AIDS Vaccines; Adult; Antibody Formation; B-Lymphocytes; Female; HIV Antibodies; HIV Infections; HIV-1; Humans; Immunoglobulin G; Male; Middle Aged; env Gene Products, Human Immunodeficiency Virus
PubMed: 33290394
DOI: 10.1371/journal.ppat.1009101 -
International Journal of Environmental... May 2022High participant retention is essential to achieve adequate statistical power for clinical trials. We assessed participant retention and predictors of loss to follow-up... (Review)
Review
BACKGROUND
High participant retention is essential to achieve adequate statistical power for clinical trials. We assessed participant retention and predictors of loss to follow-up (LTFU) in an HIV vaccine-preparedness study in Masaka, Uganda.
METHODS
Between July 2018 and March 2021, HIV sero-negative adults (18-45 years) at high risk of HIV infection were identified through HIV counselling and testing (HCT) from sex-work hotspots along the trans-African highway and fishing communities along the shores of Lake Victoria. Study procedures included collection of baseline socio-demographic data, quarterly HCT, and 6-monthly collection of sexual risk behaviour data. Retention strategies included collection of detailed locator data, short clinic visits (1-2 h), flexible reimbursement for transport costs, immediate (≤7 days) follow-up of missed visits via phone and/or home visits, and community engagement meetings. LTFU was defined as missing ≥2 sequential study visits. Poisson regression models were used to identify baseline factors associated with LTFU.
RESULTS
672 participants were included in this analysis. Of these, 336 (50%) were female and 390 (58%) were ≤24 years. The median follow-up time was 11 months (range: 0-31 months). A total 214 (32%) participants were LTFU over 607.8 person-years of observation (PYO), a rate of 35.2/100 PYO. LTFU was higher in younger participants (18-24 years versus 35-45 years, adjusted rate ratio (aRR) = 1.29, 95% confidence interval (CI) 0.80-2.11), although this difference was not significant. Female sex (aRR = 2.07, 95% CI, 1.51-2.84), and recreational drug use (aRR = 1.61, 95% CI, 1.12-2.34) were significantly associated with increased LTFU. Engagement in transactional sex was associated with increased LTFU (aRR = 1.36, 95% CI, 0.97-1.90) but this difference was not significant. LTFU was higher in 2020-2021 (the period of COVID-19 restrictions) compared to 2018-2019 (aRR = 1.54, 1.17-2.03). Being Muslim or other (aRR = 0.68, 95% CI 0.47-0.97) and self-identification as a sex worker (aRR = 0.47, 95% CI, 0.31-0.72) were associated with reduced LTFU.
CONCLUSION
We observed a high LTFU rate in this cohort. LTFU was highest among women, younger persons, recreational drug users, and persons who engage in transactional sex. Efforts to design retention strategies should focus on these subpopulations.
Topics: AIDS Vaccines; Adult; COVID-19; Female; Follow-Up Studies; HIV Infections; Humans; Male; Uganda
PubMed: 35681962
DOI: 10.3390/ijerph19116377 -
Heliyon Jan 2021The HIV Vaccine Trials Network (HVTN) is the world's largest publicly funded, multi-disciplinary international collaboration facilitating the development of vaccines to...
The HIV Vaccine Trials Network (HVTN) is the world's largest publicly funded, multi-disciplinary international collaboration facilitating the development of vaccines to prevent HIV/AIDS and has conducted the vast majority of HIV/AIDS clinical trials since its inception in 1999. Although scientific findings from the program have been published in scholarly journals, the impact of a large scientific research network such as the HVTN on the HIV/AIDS vaccine field has not been assessed. This paper describes and elucidates the productivity, influence, and collaboration among HVTN researchers over the last two decades. Our analyses indicate that the HVTN has funded a large number of HIV/AIDS vaccine safety and efficacy clinical trials through a strong global network of clinical sites. In addition, several metrics indicate HVTN researchers also published original research articles that are influential in the HIV vaccine field. Scientific research collaboration is critically important in a complex and multidisciplinary field such as HIV vaccine development as it allows improved sharing of knowledge and expertise as well as the pooling of resources and data. We found that collaboration in the HIV vaccine field increased during this time period and collaboration among HVTN authors increased even more. Combining these productivity, influence, and collaboration metrics with research outcomes can provide a comprehensive assessment of large complex programs such as the HVTN.
PubMed: 33532641
DOI: 10.1016/j.heliyon.2021.e06005 -
Human Vaccines & Immunotherapeutics Dec 2022Despite recent advances in human immunodeficiency virus-1 (HIV-1) prevention, a fast, safe, and effective vaccine will probably be necessary to end the HIV/AIDS...
BACKGROUND
Despite recent advances in human immunodeficiency virus-1 (HIV-1) prevention, a fast, safe, and effective vaccine will probably be necessary to end the HIV/AIDS pandemic. This study was conducted to evaluate global research trends and map the key bibliometric indices in HIV-1 genetic diversity from 1998 to 2021.
METHODS
A comprehensive online search was conducted in the Web of Science Core Collection database to retrieve published literature on HIV-1 genetic diversity. Key bibliometric indicators were calculated and evaluated using HistCite, Bibliometrix: An R-tool, and VOSviewer software for windows.
RESULTS
A total of 2,060 documents written by 9,201 authors and published in 250 journals were included in the final analysis. Year 2012 was the most productive year with 121 (5.87%) publications. The most prolific author was Shao Yiming (n = 74, 3.59%) from Chinese Center for Disease Control and Prevention. The United States of America was the highly contributing and influential country (n = 681, 33.05%). was the most productive journal (n = 562, 27.2%). Network visualization shows that HIV-1 was the most widely used author keyword.
CONCLUSION
This study provides global research trends and detailed information on HIV-1 genetic diversity. The amount of scientific literature on HIV-1 genetic diversity research has rapidly increased in the last two decades. The maximum number of articles on HIV-1 genetic diversity was published in developed countries; therefore, a scientific research collaboration among researchers and institutes in low-income countries should be promoted and supported.
Topics: AIDS Vaccines; Bibliometrics; Genetic Variation; HIV-1; Humans; Retrospective Studies; United States
PubMed: 35016590
DOI: 10.1080/21645515.2021.2014733 -
Indian Journal of Community Medicine :... 2023Approximately 40 years have passed since we first learned about the human immunodeficiency virus (HIV), but several people living with HIV (PLHIV) in developing...
INTRODUCTION
Approximately 40 years have passed since we first learned about the human immunodeficiency virus (HIV), but several people living with HIV (PLHIV) in developing countries such as India cannot avail treatments. This makes preventive measures, such as vaccinations, critical in these persons to avoid vaccine preventable diseases (VPDs). However, little is known about the willingness and perceptions of PLHIV regarding these vaccines. Therefore, we explored vaccine awareness and hesitancy, especially during the recent COVID-19 pandemic.
OBJECTIVES
The primary objective was to determine the uptake of the Covid-19 vaccine and other VPD's among PLHIV and factors affecting the same in Antiretroviral therapy (ART) centers in a tertiary care hospital in North India.
RESEARCH DESIGN AND METHODS
This was a cross-sectional study of HIV patients who attended our Antiretroviral Therapy center (ART). Clinical data were collected using a questionnaire on general profile, disease information, knowledge, attitude, and practice (KAP) regarding vaccinations, and vaccination status for different VPDs.
RESULTS/FINDINGS
We enrolled 300 subjects and found that 82% of the patients attending our ART center were aware of vaccinations, most of whom were aware of the polio vaccine (=91, 30.33%), followed by tuberculosis (=61, 20.33%), and the majority of them were not aware of vaccines indicated in PLHIV. We also found that the majority (= 240, 80.23%) of patients had vaccine hesitancy, especially regarding the new COVID-19 vaccine.
CONCLUSION
There is a need to create awareness among people about the benefits and uses of vaccination to achieve the greater goal of reduced morbidity and mortality among PLHIV. There is a need for free vaccination programs for VPDs in PLHIV patients.
PubMed: 37469920
DOI: 10.4103/ijcm.ijcm_901_22