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Journal of Virology Apr 2022With the much-debated exception of the modestly reduced acquisition reported for the RV144 efficacy trial, HIV-1 vaccines have not protected humans against infection,... (Review)
Review
With the much-debated exception of the modestly reduced acquisition reported for the RV144 efficacy trial, HIV-1 vaccines have not protected humans against infection, and a vaccine of similar design to that tested in RV144 was not protective in a later trial, HVTN 702. Similar vaccine regimens have also not consistently protected nonhuman primates (NHPs) against viral acquisition. Conversely, experimental vaccines of different designs have protected macaques from viral challenges but then failed to protect humans, while many other HIV-1 vaccine candidates have not protected NHPs. While efficacy varies more in NHPs than humans, vaccines have failed to protect in the most stringent NHP model. Intense investigations have aimed to identify correlates of protection (CoPs), even in the absence of net protection. Unvaccinated animals and humans vary vastly in their susceptibility to infection and in their innate and adaptive responses to the vaccines; hence, merely statistical associations with factors that do not protect are easily found. Systems biological analyses, including artificial intelligence, have identified numerous candidate CoPs but with no clear consistency within or between species. Proposed CoPs sometimes have only tenuous mechanistic connections to immune protection. In contrast, neutralizing antibodies (NAbs) are a central mechanistic CoP for vaccines that succeed against other viruses, including SARS-CoV-2. No HIV-1 vaccine candidate has yet elicited potent and broadly active NAbs in NHPs or humans, but narrow-specificity NAbs against the HIV-1 isolate corresponding to the immunogen do protect against infection by the autologous virus. Here, we analyze why so many HIV-1 vaccines have failed, summarize the outcomes of vaccination in NHPs and humans, and discuss the value and pitfalls of hunting for CoPs other than NAbs. We contrast the failure to find a consistent CoP for HIV-1 vaccines with the identification of NAbs as the principal CoP for SARS-CoV-2.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; Artificial Intelligence; COVID-19 Vaccines; Data Interpretation, Statistical; HIV Infections; HIV-1; Humans; SARS-CoV-2
PubMed: 35384694
DOI: 10.1128/jvi.00034-22 -
Science Translational Medicine Oct 2019Potent broadly neutralizing antibodies may be used to treat or prevent HIV and to help guide HIV vaccine design. (Review)
Review
Potent broadly neutralizing antibodies may be used to treat or prevent HIV and to help guide HIV vaccine design.
Topics: AIDS Vaccines; Broadly Neutralizing Antibodies; Clinical Trials as Topic; HIV Antibodies; HIV Infections; Humans; Immunization
PubMed: 31666399
DOI: 10.1126/scitranslmed.aaz2686 -
Frontiers in Immunology 2019Before the development of the first vaccine, infectious diseases were a major cause of death around the globe with life expectancy estimated to be <50 years. Three... (Review)
Review
Before the development of the first vaccine, infectious diseases were a major cause of death around the globe with life expectancy estimated to be <50 years. Three measures have helped to drastically reduce the burden of infectious diseases but only vaccines have proven to be able to eradicate infectious agents. Herein, we describe new methodologies that have paved the way for what is currently known as modern vaccinology and the use of vaccines to tackle antimicrobial resistance, the biggest global threat of our time.
Topics: AIDS Vaccines; Antibodies, Monoclonal; Antibodies, Neutralizing; Antigens; B-Lymphocytes; Clinical Trials as Topic; Communicable Diseases, Emerging; Disease Outbreaks; Drug Resistance, Microbial; Genetic Engineering; Global Health; History, 19th Century; History, 20th Century; History, 21st Century; History, Ancient; History, Medieval; Immunotherapy, Active; Respiratory Syncytial Virus Vaccines; Single-Cell Analysis; Vaccination; Vaccines
PubMed: 31404139
DOI: 10.3389/fimmu.2019.01722 -
Cell Reports Mar 2022The success of nucleoside-modified mRNAs in lipid nanoparticles (mRNA-LNP) as COVID-19 vaccines heralded a new era of vaccine development. For HIV-1, multivalent...
The success of nucleoside-modified mRNAs in lipid nanoparticles (mRNA-LNP) as COVID-19 vaccines heralded a new era of vaccine development. For HIV-1, multivalent envelope (Env) trimer protein nanoparticles are superior immunogens compared with trimers alone for priming of broadly neutralizing antibody (bnAb) B cell lineages. The successful expression of complex multivalent nanoparticle immunogens with mRNAs has not been demonstrated. Here, we show that mRNAs can encode antigenic Env trimers on ferritin nanoparticles that initiate bnAb precursor B cell expansion and induce serum autologous tier 2 neutralizing activity in bnAb precursor V + V knock-in mice. Next-generation sequencing demonstrates acquisition of critical mutations, and monoclonal antibodies that neutralize heterologous HIV-1 isolates are isolated. Thus, mRNA-LNP can encode complex immunogens and may be of use in design of germline-targeting and sequential boosting immunogens for HIV-1 vaccine development.
Topics: AIDS Vaccines; Animals; Antibodies, Monoclonal; Antibodies, Neutralizing; COVID-19; COVID-19 Vaccines; Epitopes; Ferritins; HIV Antibodies; HIV-1; Humans; Liposomes; Mice; Nanoparticles; RNA, Messenger; env Gene Products, Human Immunodeficiency Virus
PubMed: 35294883
DOI: 10.1016/j.celrep.2022.110514 -
Expert Review of Vaccines Nov 2019: Despite intensive research efforts, there is still no effective prophylactic vaccine available against HIV-1. Currently, substantial efforts are devoted to the... (Review)
Review
: Despite intensive research efforts, there is still no effective prophylactic vaccine available against HIV-1. Currently, substantial efforts are devoted to the development of vaccines aimed at inducing broadly neutralizing antibodies (bNAbs), which are capable of neutralizing most HIV-1 strains. All bNAbs target the HIV-1 envelope glycoprotein (Env), but Env immunizations usually only induce neutralizing antibodies (NAbs) against the sequence-matched virus and not against other strains.: We describe the different strategies that have been explored to improve the breadth and potency of anti-HIV-1 NAb responses. The discussed strategies include the application of engineered Env immunogens, optimization of (bNAb) epitopes, different cocktail and sequential vaccination strategies, nanoparticles and nucleic acid-based vaccines.: A combination of the strategies described in this review and future approaches are probably needed to develop an effective HIV-1 vaccine that can induce broad, potent and long-lasting NAb responses.
Topics: AIDS Vaccines; Antibodies, Neutralizing; Antibody Formation; HIV Antibodies; HIV-1; Humans; Treatment Outcome; env Gene Products, Human Immunodeficiency Virus
PubMed: 31791150
DOI: 10.1080/14760584.2019.1690458 -
Frontiers in Immunology 2021Innate immunity modulates adaptive immunity and defines the magnitude, quality, and longevity of antigen-specific T- and B- cell immune memory. Various vaccine and...
Innate immunity modulates adaptive immunity and defines the magnitude, quality, and longevity of antigen-specific T- and B- cell immune memory. Various vaccine and administration factors influence the immune response to vaccination, including the route of vaccine delivery. We studied the dynamics of innate cell responses in blood using a preclinical model of non-human primates immunized with a live attenuated vaccinia virus, a recombinant Modified vaccinia virus Ankara (MVA) expressing a fusion of HIV-1, and mass cytometry. We previously showed that it induces a strong, early, and transient innate response, but also late phenotypic modifications of blood myeloid cells after two months when injected subcutaneously. Here, we show that the early innate effector cell responses and plasma inflammatory cytokine profiles differ between subcutaneous and intradermal vaccine injection. Additionally, we show that the intradermal administration fails to induce more highly activated/mature neutrophils long after immunization, in contrast to subcutaneous administration. Different batches of antibodies, staining protocols and generations of mass cytometers were used to generate the two datasets. Mass cytometry data were analyzed in parallel using the same analytical pipeline based on three successive clustering steps, including SPADE, and categorical heatmaps were compared using the Manhattan distance to measure the similarity between cell cluster phenotypes. Overall, we show that the vaccine is not sufficient for the late phenotypic modifications of innate myeloid cells, which are evocative of innate immune training. Its route of administration is also crucial, likely by influencing the early innate response, and systemic inflammation, and vaccine biodistribution.
Topics: AIDS Vaccines; Animals; Cytokines; HIV Antibodies; HIV-1; Macaca fascicularis; Male; Neutrophils; Vaccinia virus
PubMed: 35058925
DOI: 10.3389/fimmu.2021.784813 -
Journal of the International AIDS... Nov 2021A primary focus of HIV-1 vaccine development is the activation of B cell receptors for naïve or precursor broadly neutralizing antibodies (bnAbs), followed by expansion... (Review)
Review
INTRODUCTION
A primary focus of HIV-1 vaccine development is the activation of B cell receptors for naïve or precursor broadly neutralizing antibodies (bnAbs), followed by expansion and maturation of bnAb B cell lineage intermediates leading to highly affinity-matured bnAbs. HIV-1 envelope (Env) encodes epitopes for bnAbs of different specificities. Design of immunogens to induce bnAb precursors of different specificities and mature them into bnAb status is a goal for HIV-1 vaccine development. We review vaccine strategies for bnAb lineages development and highlight the immunological barriers that these strategies must overcome to generate bnAbs.
METHODS
We provide perspectives based on published research articles and reviews.
DISCUSSION
The recent Antibody Mediated Protection (AMP) trial that tested the protective efficacy of one HIV-1 Env bnAb specificity demonstrated that relatively high levels of long-lasting serum titers of multiple specificities of bnAbs will be required for protection from HIV-1 transmission. Current vaccine efforts for induction of bnAb lineages are focused on immunogens designed to expand naïve HIV-1 bnAb precursor B cells following the recent success of vaccine-induction of bnAb precursor B cells in macaques and humans. BnAb precursor B cells serve as templates for priming-immunogen design. However, design of boosting immunogens for bnAb maturation requires knowledge of the optimal immunogen design and immunological environment for bnAb B cell lineage affinity maturation. BnAb lineages acquire rare genetic changes as mutations during B cell maturation. Moreover, the immunological environment that supports bnAb development during HIV-1 infection is perturbed with an altered B cell repertoire and dysfunctional immunoregulatory controls, suggesting that in normal settings, bnAb development will be disfavoured. Thus, strategies for vaccine induction of bnAbs must circumvent immunological barriers for bnAb development that normally constrain bnAb B cell affinity maturation.
CONCLUSIONS
A fully protective HIV-1 vaccine needs to induce durable high titers of bnAbs that can be generated by a sequential set of Env immunogens for expansion and maturation of bnAb B cell lineages in a permitted immunological environment. Moreover, multiple specificities of bnAbs will be required to be sufficiently broad to prevent the escape of HIV-1 strains during transmission.
Topics: AIDS Vaccines; Antibodies, Neutralizing; Broadly Neutralizing Antibodies; HIV Antibodies; HIV Infections; HIV-1; Humans; env Gene Products, Human Immunodeficiency Virus
PubMed: 34806332
DOI: 10.1002/jia2.25831 -
Cell Host & Microbe Sep 2022Strain 68-1 rhesus cytomegalovirus expressing simian immunodeficiency virus (SIV) antigens (RhCMV/SIV) primes MHC-E-restricted CD8+ T cells that control SIV replication...
Strain 68-1 rhesus cytomegalovirus expressing simian immunodeficiency virus (SIV) antigens (RhCMV/SIV) primes MHC-E-restricted CD8+ T cells that control SIV replication in 50%-60% of the vaccinated rhesus macaques. Whether this unconventional SIV-specific immunity and protection is unique to rhesus macaques or RhCMV or is intrinsic to CMV remains unknown. Here, using cynomolgus CMV vectors expressing SIV antigens (CyCMV/SIV) and Mauritian cynomolgus macaques, we demonstrate that the induction of MHC-E-restricted CD8+ T cells requires matching CMV to its host species. RhCMV does not elicit MHC-E-restricted CD8+ T cells in cynomolgus macaques. However, cynomolgus macaques vaccinated with species-matched 68-1-like CyCMV/SIV mounted MHC-E-restricted CD8+ T cells, and half of the vaccinees stringently controlled SIV post-challenge. Protected animals manifested a vaccine-induced IL-15 transcriptomic signature that is associated with efficacy in rhesus macaques. These findings demonstrate that the ability of species-matched CMV vectors to elicit MHC-E-restricted CD8+ T cells that are required for anti-SIV efficacy is conserved in nonhuman primates, and these data support the development of HCMV/HIV for a prophylactic HIV vaccine.
Topics: AIDS Vaccines; Animals; CD8-Positive T-Lymphocytes; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Vaccines; Interleukin-15; Macaca fascicularis; Macaca mulatta; SAIDS Vaccines; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus
PubMed: 35981532
DOI: 10.1016/j.chom.2022.07.013 -
BMC Medical Ethics Dec 2022For over 35 years, Africa has continued to host HIV vaccine trials geared towards overturning the HIV/AIDs pandemic in the continent. However, the methods of sharing...
BACKGROUND
For over 35 years, Africa has continued to host HIV vaccine trials geared towards overturning the HIV/AIDs pandemic in the continent. However, the methods of sharing the vaccines, when available remain less certain. Therefore, the study aims to explore stakeholders' perspectives in the global South, in this case, Tanzania, on how HIV vaccines ought to be fairly shared.
METHODS
The study deployed a qualitative case study design. Data were collected through in-depth interviews and focus group discussions with a total of 37 purposively selected participants. This included researchers, institutional review board members, a policymaker, HIV/AIDS advocates, and community advisory board members. The data obtained were inductively and deductively analyzed.
RESULTS
Findings indicate that HIV vaccines can be shared fairly under the principles of distributive justice (contribution, need and equality). Thus, contribution-based sharing ought to be utilized upon the necessity to prioritize vaccine access or subsidized trial benefits to host communities. Need-based sharing ought to be considered for non-host communities that are at an increased risk of HIV infection. Lastly, equal-based sharing would be useful at later stages of vaccine distribution or when the aforementioned principles are deemed morally inappropriate. However, none of the benefit-sharing approaches is free of limitations and a counterbalancing sense of unfairness.
CONCLUSION
Fair sharing of HIV vaccines, when available, ought to be informed by the contribution, need and equality principles of distributive justice. Countries in the global south including Tanzania are likely to be prioritized during the distribution of the HIV vaccines due to their participation in HIV vaccine trials and due to the disproportionate HIV burden evident in the region.
Topics: Humans; AIDS Vaccines; Acquired Immunodeficiency Syndrome; HIV Infections; Tanzania; Ethics Committees, Research
PubMed: 36522782
DOI: 10.1186/s12910-022-00874-w -
Frontiers in Immunology 2019Antibodies (Abs) are the major component of the humoral immune response and a key player in vaccination. The precise Ab-mediated inhibitory mechanisms leading to... (Review)
Review
Antibodies (Abs) are the major component of the humoral immune response and a key player in vaccination. The precise Ab-mediated inhibitory mechanisms leading to protection against HIV have not been elucidated. In addition to the desired viral capture and neutralizing Ab functions, complex Ab-dependent mechanisms that involve engaging immune effector cells to clear infected host cells, immune complexes, and opsonized virus have been proposed as being relevant. These inhibitory mechanisms involve Fc-mediated effector functions leading to Ab-dependent cellular cytotoxicity, phagocytosis, cell-mediated virus inhibition, aggregation, and complement inhibition. Indeed, the decreased risk of infection observed in the RV144 HIV-1 vaccine trial was correlated with the production of non-neutralizing inhibitory Abs, highlighting the role of Ab inhibitory functions besides neutralization. Moreover, Ab isotypes and subclasses recognizing specific HIV envelope epitopes as well as pecular Fc-receptor polymorphisms have been associated with disease progression. These findings further support the need to define which Fc-mediated Ab inhibitory functions leading to protection are critical for HIV vaccine design. Herein, based on our previous review Su & Moog Front Immunol 2014, we update the different inhibitory properties of HIV-specific Abs that may potentially contribute to HIV protection.
Topics: AIDS Vaccines; Antibodies, Neutralizing; Antibody-Dependent Cell Cytotoxicity; HIV Antibodies; HIV Infections; HIV-1; Humans; Immunoglobulin Fc Fragments
PubMed: 31921207
DOI: 10.3389/fimmu.2019.02968