Trends and perspectives in the HIV vaccine research over the past thirty-five years: A scientometrics analysis through CiteSpace.

More Surprises in the Development of an HIV Vaccine (General Commentary)

Despite extensive research efforts, a preventive human immunodeficiency virus (HIV) vaccine remains one of the major challenges in the field of AIDS research. Experimental strategies which have been proven successful for other viral vaccines are not enough to tackle HIV-1 and new approaches to design effective preventive AIDS vaccines are of utmost importance. Due to enormous diversity among global circulating HIV strains, an effective HIV vaccine must elicit broadly protective antibodies based responses; therefore discovering new broadly neutralizing antibodies (bNAbs) against HIV has become major focus in HIV vaccine research. However further understanding of the viral targets of such antibodies and mechanisms of action of bNAbs is required for advancement of HIV vaccine research. This technical note discusses our current knowledge on the bNAbs and immunoprophylaxis using viral vectors with their relevance in designing of new candidates to HIV-1 vaccines.

Prior research has documented a high prevalence of conspiracy beliefs about the origin of the human immunodeficiency virus (HIV) and the role of the government in the acquired immunodeficiency syndrome (AIDS) epidemic, particularly among racial and ethnic minorities in the United States. Whether such beliefs are a barrier to participation in HIV prevention research is not known. To understand the prevalence of HIV conspiracy beliefs and their relationship to willingness to participate in HIV vaccine research among three racial/ethnic groups. Cross-sectional survey. Six hundred and one community-recruited volunteers (33.0 % White, 32.5 % Mexican American, and 34.5 % African American). We evaluated the level of agreement with six previously described HIV conspiracy beliefs, trust in medical research, and willingness to participate in HIV vaccine research. Multivariate models were used to compare these parameters among the three racial/ethnic groups while controlling for the potential confounding effects of socioeconomic status, access to health care, and other demographic factors. African Americans, Mexican Americans, and whites had similar levels of distrust in medical research. African and Mexican Americans were more likely to endorse one or more of six HIV conspiracy beliefs than whites (59.0 % and 58.6 % versus 38.9 %, respectively, P < 0.001), but were significantly more willing to participate in HIV vaccine research (ORs 1.58, CI 1.10-2.25 and 2.53, CI 1.75-3.66, respectively). Among respondents of all racial/ethnic groups, endorsing HIV conspiracy beliefs was not associated with willingness to participate in research. HIV conspiracy beliefs, while common among all racial and ethnic groups in the United States, do not preclude willingness to participate in HIV prevention research.

Young men who have sex with men’s awareness, acceptability, and willingness to participate in HIV vaccine trials: Results from a nationwide online pilot study

An HIV (human immunodeficiency virus) vaccine is needed to combat the 1–2 million cases on new HIV infection each year. The goal of vaccination is to establish long‐term immunological readiness that allows rapid protection against infectious disease. All current successful vaccines achieve this by inducing neutralising antibodies, which are effective against acute, cytopathic infections that could otherwise prove fatal. By contrast, potential vaccines against highly variable pathogens that establish persistent infections, such as HIV, have had limited success. There have been multiple attempts to induce effective immunity to HIV in humans, with only one approach showing partial (31%) efficacy. Several clues on a better path forward have, however, emerged from HIV vaccine trials in humans, studies of humans who naturally control HIV infection and studies in animal models. There has been an improved understanding of anti‐HIV neutralising antibodies, which, if could be induced successfully, are likely to be highly effective. Antibodies that engage Fc receptors on innate immune cells (the so‐called ADCC (antibody‐dependent cellular cytotoxicity) antibodies) have emerged as a key component of successful vaccine strategies. New vaccine design and delivery strategies are now entering large‐scale human efficacy trials. These approaches offer real hope that a safe and effective HIV vaccine will eventually be developed to assist in the control of the HIV/AIDS (acquired immunodeficiency syndrome) pandemic. Key Concepts A HIV vaccine is urgently needed. There are many hurdles to induce effective HIV immunity. Only one HIV vaccine trial in humans has showed partial efficacy to date. Neutralising antibodies against HIV are highly effective in animal models but are difficult to induce by vaccination. Functional anti‐HIV antibodies that can engage innate immune cells to fight HIV are likely to be a key component of successful HIV vaccine strategies. T‐cell‐based immunity against HIV shows promise in certain settings. New HIV vaccines are entering human efficacy trials. There is considerable promise that an effective HIV vaccine will be developed in the future.

Although a large number of preventative human immunodeficiency virus (HIV) vaccine trials have been carried out during the last 30 years, it is remarkable that an effective HIV vaccine has not yet been developed. Research paradigms correspond to theoretical assumptions and particular strategies that scientists use when they try to solve a particular problem. Many paradigms used successfully in vaccinology were ineffective with HIV. For instance: 1) The structure-based reverse vaccinology approach failed because investigators tried to generate a vaccine starting with the antigenic structure of HIV-envelope (Env) epitopes bound to neutralizing monoclonal antibodies (mAbs) derived from HIV-infected individuals. They assumed that this antigenic structure would also possess the immunogenic capacity of inducing in vaccinees a polyclonal antibody (Ab) response with the same neutralizing capacity as the mAb. 2) The structures observed in epitope-paratope crystallographic complexes result from mutually induced fit between the two partners and do not correspond to the structures present in the free molecules before they had interacted. 3) The affinity-matured neutralizing mAbs obtained from chronically infected individuals did not recognize the germline predecessors of these Abs present in vaccinees. 4) The HIV p17 matrix protein that lines the inner surface of the viral membrane is one of the most disordered proteins identified on our planet and this prevents the induced Abs from binding to the glycosylated HIV gp120 protein. 5) Vaccinologists need to solve so-called inverse problems, for instance, guessing what are the multiple causes that produced an earlier wanted beneficial effect such as the absence of deleterious HIV infection in elite controllers. Since the immune system consists of numerous subsystems that have not yet been elucidated, it is impossible to solve the inverse problems posed by each subsystem. 6) Vaccinology is an empirical science that only sometimes succeeds because we do not understand the complex mechanisms that lead to protective immune responses.

All current human immunodeficiency virus (HIV) vaccine candidates contain multiple viral components and elicit antibodies that react positively in licensed HIV diagnostic tests, which contain similar viral products. Thus, vaccine trial participants could be falsely diagnosed as infected with HIV. Additionally, uninfected, seropositive vaccinees may encounter long-term social and economic harms. Moreover, this also interferes with early detection of true HIV infections during preventive HIV vaccine trials. An HIV-seropositive test result among uninfected vaccine trial participants is a major public health concern for volunteers who want to participate in future HIV vaccine trials. Based on the increased number of HIV vaccines being tested globally, it is essential to differentiate vaccine- from virus-induced antibodies. Using a whole-HIV-genome phage display library, we identified conserved sequences in Env-gp41 and Gag-p6 which are recognized soon after infection, do not contain protective epitopes, and are not part of most current HIV vaccines. We established a new HIV serodetection assay based on these peptides. To date, this assay, termed HIV-SELECTEST, demonstrates >99% specificity and sensitivity. Importantly, in testing of plasma samples from multiple HIV vaccine trials, uninfected trial participants scored negative, while all intercurrent infections were detected within 1 to 3 months of HIV infection. The new HIV-SELECTEST is a simple but robust diagnostic tool for easy implementation in HIV vaccine trials and blood banks worldwide.

Experimental simian immunodeficiency virus and human immunodeficiency virus (HIV) vaccines have been shown to induce protective immunity in macaques and chimpanzees, respectively. Immunologic correlates of protection have not been established, although in the case of HIV vaccines, gp120-, V3-specific neutralizing antibodies may be involved. V3 sequences are strain specific, and the genetic and antigenic variability of HIV may present an obstacle for vaccine development. However, in addition to anti-V3 antibodies, the immune response to HIV infection (and immunization) involves group-specific neutralizing antibodies directed against conformational epitopes in the gpl20-CD4 binding site, as well as an array of cell-mediated immune responses against several HIV proteins. Safety and immunogenicity human trials (Phase l/ll) of 12 candidate vaccines tested in HIV-negative volunteers have shown that, in general, they are well tolerated and induce neutralizing antibodies and different cell-mediated responses. Safety and immunogenicity trials of four candidate vaccines in HIV-infected volunteers have shown that they are safe and capable of increasing anti-HIV immune responses, although no information has been obtained on potential clinical benefits. Criteria for initiating efficacy (Phase III) trials of preventive candidate vaccines are being discussed by the scientific community, and appropriate study populations are being identified and prepared by industrialized and developing countries through collaboration with the World Health Organization and other national and international HIV vaccine research programs.

Background: Human immunodeficiency virus (HIV) remains a global health challenge despite significant advancements in antiretroviral therapy and prevention strategies. Developing a safe and effective vaccine that protects people worldwide has been a major goal, yet the genetic variability and rapid mutation rate of the virus continue to pose substantial challenges. Methods: In this review paper, we aim to provide a comprehensive review of previous vaccine candidates and the progress made in HIV vaccine clinical trials, spanning from the late 1990s to 2025. PubMed and ClinicalTrials.gov were searched for English-language Phase 1–3 HIV vaccine trials published from 1990 to March 2025. After de-duplication, titles/abstracts and then full texts were screened; trial phase, regimen, immunogenicity, efficacy, and correlates were extracted into a structured spreadsheet. Owing to platform heterogeneity, findings were synthesized narratively and arranged chronologically to trace the evolution of vaccine strategies. Results: Early vaccine trials demonstrated that a protein subunit vaccine failed to protect against infection, revealing the complexity of HIV evasion strategies and shifting the focus to a comprehensive immune response, including both antibody and T-cell responses. Trials evaluating the role of viral vectors in generating cell-mediated immunity were also insufficient, and suggested that targeting T cell response alone was not enough. In 2009, the RV144 trial made a breakthrough by showing partial protection against HIV infection and providing the first indication of efficacy. This partial success influenced subsequent trials, prompting researchers to further explore the complex immune response required for protection and consider combinations of vaccine technologies to achieve robust, long-lasting immunity. Conclusion: Despite setbacks, decades of rigorous efforts have provided significant contributions to HIV vaccine discovery and development, offering hope for preventing and protecting against HIV infection. The field remains active by continuing to advance our understanding of the virus, refining vaccine strategies, and employing novel technologies.

Several studies have suggested that interleukin (IL)-15 is a promising adjuvant that promotes cellular immunity when administered with human immunodeficiency virus (HIV) vaccine. Here we evaluated the effect of IL-15 plasmid on HIV-specific immune responses, especially cellular immunity, in eight rhesus monkeys. These monkeys were immunized three times with HIV DNA vaccine with or without IL-15 plasmid and boosted with recombinant Tiantan strain vaccinia virus-based HIV vaccine (rTV) 22 weeks after the first immunization. Although we did not detect any significant differences in the HIV-specific CD8(+) T-cell response between monkeys with IL-15 coimmunization and monkeys with HIV vaccine alone, our results showed that the frequency of effector CD8(+) memory T cells in the peripheral blood was significantly higher in monkeys with IL-15 coimmunization than those with HIV vaccine alone at almost all of the time points examined. Furthermore, the titers of anti-HIV antibodies were higher in Group T than those in Group C after rTV boosting. These findings in rhesus monkeys suggest that IL-15 may be useful as a cytokine adjuvant for HIV vaccine.

Initial human immunodeficiency virus (HIV) vaccines are unlikely to prevent acquisition of HIV in all recipients. Moreover, several HIV vaccines are under evaluation that are designed to reduce viremia after acquisition of infection. Such vaccines could provide important benefits to delay HIV progression and to reduce transmission. The decision to license a vaccine on the basis of observed effects on virus load and other postinfection surrogate end points in an efficacy trial is complicated by uncertainty about whether the vaccine effects will persist and reliably predict clinical effects, and by the challenge in interpreting the data posed by treatment of some seroconverters with antiretroviral drugs. Here, we evaluate how analyses of certain surrogate end points can be used for inferring clinically significant vaccine effects and propose end points that could be evaluated in efficacy trials to support licensure. The assessment suggests that a vaccine demonstrating moderately durable effects to delay therapy and to ameliorate viremia merits consideration for licensure.

Despite the tremendous efforts to develop a successful human immunodeficiency virus (HIV) vaccine, the quest for a safe and effective HIV vaccine seems to be remarkably long and winding. Disappointing results from previous clinical trials of VaxGen's AIDSVAXgp120 vaccine and MRKAd5 HIV-1 Gag/Pol/Nef vaccine emphasize that understanding the correlates of immune protection in HIV infection is the key to solve the puzzle. The modest vaccine efficacy from RV144 trial and the successive results obtained from the correlate of risk analysis have reinvigorated the HIV vaccine research field leading to various novel strategies. This paper will review the brief history and recent advances in HIV vaccine development.

Chapter 27. HIV Vaccine Development: From Empiricism to Medicinal Chemistry

Chapter 39 - Progress in the Development and Testing of HIV Vaccines

A human immunodeficiency virus (HIV) vaccine is of high importance for the control of the current pandemic. Outside of screening blood, male circumcision and drug treatment of mothers and infants at birth, the effectiveness of public health measures have been limited by compliance and cost. Particularly important in the path towards an HIV vaccine has been the Thai RV144 efficacy trials, which demonstrated that priming with a recombinant canary poxvirus (ALVAC) and boosting with ALVAC plus gp120 protein provided partial protection against HIV. In RV144, a non-neutralizing antibody was associated with reduced risk. Non-neutralizing antibodies, which can directly block infection, distinguish themselves from neutralizing antibodies by mediating protection via the fragment crystallizable (Fc) regions of bound antibody, triggering killing by innate immune responses, such as antibody-dependent cellular cytotoxicity, phagocytosis and complement-mediated killing. GeoVax (Atlanta, GA, USA) has developed clade B vaccines that have undergone phase I and IIa clinical testing in the Americas through the HIV Vaccine Trials Network.