On January 13, 2026, the National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. National Institutes of Health (NIH), convened a virtual workshop to examine how advances in preventive and therapeutic HIV research can be leveraged synergistically to develop immune-based strategies to protect against HIV infection and/or disease progression. The primary objective was to review data from leading prevention trials conducted in people living without HIV and to assess how emerging strategies might be translated and evaluated in clinical studies involving people living with HIV to inform both prevention and therapeutic intervention development. Participants discussed recent immunogen design, immune monitoring, and intervention approaches relevant to both prevention and therapeutic-directed research. Here, we summarize the key findings presented at the workshop and identify scientific priorities and knowledge gaps to accelerate the development of effective immune-based strategies against HIV.

Despite recent advances in other prevention strategies, an effective vaccine is still needed to guarantee a sustained end to the HIV/AIDS pandemic. However, the traditional ap-proaches of vaccinology have thus far failed to produce an effective vaccine. More basic research may be needed to enhance our understanding of HIV immunity and the immunological principles behind vaccination and to leverage advanced technologies before applied research activities can be successfully used to develop a distributable HIV vaccine. US Government funding plays a crucial role in promoting, enabling, and advising independent scientists and experts to perform such research. This article was written to provide, to the broader scientific community, detail about the tools NIAID uses for research funding, how and why they were used for HIV vaccine development, and how they have been helpful; it is written from the perspective of a Program Officer’s experiences while working for more than 25 years in the Division of AIDS (DAIDS) of NIAID at the NIH (the US National Institutes of Health). Several types of funding activities pro-mote HIV vaccine development efforts, but three types of such activities and their impact on HIV vaccine development will be discussed in more detail.

The US National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institute of Health (NIH), convened a virtual workshop on August 8-9 th , 2023 to explore potential synergies between HIV vaccine approaches that are designed to induce cellular or humoral immune responses. The goal of this workshop was to review data on leading vaccine candidates and to discuss the best strategies for combining these approaches to optimize immunity against HIV. Here, we summarize the findings reviewed at the workshop and discuss the knowledge gaps and priorities for future studies that will help accelerate the development of a preventive HIV vaccine.

Funding vaccine development research is more complicated than simply putting out an announcement of funds available. The funders must decide whether product development can be accomplished by purely applied research, or whether more fundamental knowledge is needed before product development can be started. If additional basic knowledge is needed, identifying the specific area of the knowledge gap can be a challenge. Additionally, when there appears to be a clear path of applied research sometimes obstacles are encountered that require a return to more basic work. After deciding on the work to be done, funders must attract the scientists with the broad range of needed skills to cover all the stages of development. Collaborations must be promoted and alliances with other funders and industry must be developed. Funders use multiple tools and strategies to accomplish these tasks with varying success.

In the past when large investments have been made in tackling narrow scientific challenges, the enormous expansion in our knowledge in one small area has had a spill-over effect on research and treatment of other diseases. The large investment in HIV vaccine development in recent years has the potential for such an effect on vaccine development for other diseases. HIV vaccine developers have experienced repeated failure using the standard approaches to vaccine development. This has forced them to consider immune responses in greater depth and detail. It has led to a recognition of the importance of epitopic specificity in both antibody and T cell responses. Also, it has led to an understanding of the importance of affinity maturation in antibody responses and the quality of T cell responses in T cell-mediated immunity. It has advanced the development of many novel vaccine vectors and vehicles that are now available for use in other vaccines. Further, it has focused attention on the impact of research funding mechanisms and community engagement on vaccine development. These developments and considerations have implications for vaccinology more generally. Some suggestions are made for investigators working on other "hard-to-develop" vaccines.

Abstract While the HIV/AIDS pandemic continues, the overall incidence of HIV infections has fallen through use of antiretroviral therapy (ART) and multiple prevention modalities. To achieve a durable end to the pandemic and avoid the requirement for daily antiretroviral medication over a lifetime, a safe and effective prophylactic vaccine remains essential. This chapter reviews current advances in prophylactic and therapeutic HIV-1 vaccine strategies and the challenges that lie ahead. Recent success in isolation of potent broadly neutralizing antibodies (bnAbs) from infected individuals, the discovery of mechanisms of bnAb induction, and progress in understanding mechanisms of CD8 T-cell killing of HIV-infected cells and the structure of the HIV envelope trimer have opened new strategies for HIV vaccine design. On the therapeutic front, the persistence of HIV reservoirs remains a formidable obstacle to achieving sustained virological remission in HIV-infected individuals after ART is discontinued. Development of a new generation of immune-based therapeutic agents might contribute to a curative intervention. The chapter closes with an overview of ethical challenges in vaccine development and clinical testing.

The Division of AIDS Vaccine Research Program funds the discovery and development of HIV/AIDS vaccine candidates. Basic researchers, having discovered a potential vaccine in the laboratory, next want to take that candidate into the clinic to test the concept in humans, to see if it translates. Many of them have heard of “cGMP” and know that they are supposed to make a “GMP product” to take into the clinic, but often they are not very familiar with what “cGMP” means and why these good practices are so important. As members of the Vaccine Translational Research Branch, we frequently get asked “can’t we use the material we made in the lab in the clinic?” or “aren’t Phase 1 studies exempt from cGMP?” Over the years, we have had many experiences where researchers or their selected contract manufacturing organizations have not applied an appropriate degree of compliance with cGMP suitable for the clinical phase of development. We share some of these experiences and the lessons learned, along with explaining the importance of cGMP, just what cGMP means, and what they can assure, in an effort to de-mystify this subject and facilitate the rapid and safe translational development of HIV vaccines.

The HIV cure agenda has rekindled interest in the development of a therapeutic HIV vaccine. An iterative clinical trial strategy that proved successful for the development of effective cancer chemotherapies in the 1960s may be applicable to the development of a CD8 T lymphocyte-based therapeutic HIV vaccine. However, while cancer chemotherapy development could begin with iterative clinical trials to improve the use of active drugs, the first step in therapeutic HIV vaccine design should be discovery of immunogen constructs with potential for activity and their optimization to meet the challenges of HIV-1 sequence diversity and human polymorphism in T cell antigen presentation. A strategy for doing this is discussed in this article. The proposed strategy relies on a major commitment by funding organizations to fund organized and coordinated manufacture and clinical testing of a series of first- and second-generation constructs to test basic concepts in product design. This is presented as an alternative to funding a more traditional competition among private manufacturers and product champions of individual, already designed products.

This article discusses HIV vaccine discovery and candidate vaccine testing in the context of current realities of funding and clinical trial practice. Lacking perfect animal models for testing candidate HIV vaccines, clinical investigators have proposed a strategy of iterative exploratory clinical trials in the model of cancer chemotherapy development. Problems with the appropriateness of this model to HIV vaccine development are discussed. Also, the future feasibility of this strategy in the context of increasing clinical trial costs and emerging new, efficacious prevention modalities is questioned. Strategies for making better use of animal models are presented as an alternative to iterative exploratory clinical efficacy testing. Some ways in which better data from preclinical studies can refine clinical product development are described. Finally, development of an HIV vaccine under the FDA's "Animal Rule" pathway to licensure when human efficacy studies are not feasible is discussed as a fall-back approach. Not making a preventive vaccine against HIV infection is simply not an option because eradication of AIDS will require a preventive vaccine.

Reliable methods for measuring human immunodeficiency virus (HIV) incidence are a high priority for HIV prevention. They are particularly important to assess the population-level effectiveness of new prevention strategies, to evaluate the community-wide impact of ongoing prevention programs, and to assess whether a proposed prevention trial can be performed in a timely and cost-efficient manner in a particular population and setting. New incidence assays and algorithms that are accurate, rapid, cost-efficient, and can be performed on easily-obtained specimens are urgently needed. On May 4, 2011, the Division of AIDS (DAIDS), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), sponsored a 1-day workshop to examine strategies for developing new assays to distinguish recent from chronic HIV infections. Participants included leading investigators, clinicians, public health experts, industry, regulatory specialists, and other stakeholders. Immune-based parameters, markers of viral sequence diversity, and other biomarkers such as telomere length were evaluated. Emerging nanotechnology and chip-based diagnostics, including algorithms for performing diverse assays on a single platform, were also reviewed. This report summarizes the presentations, panel discussions, and the consensus reached for pursuing the development of a new generation of HIV incidence assays.

Purified trypanosome endocytotic vesicles were subjected to Triton X-114 phase separation to obtain a fraction enriched in putative parasite receptors for adsorptive endocytosis. Rabbits immunized with this material produced antibodies that recognized many parasite proteins, including nonvarying epitopes on the parasite's endocytotic surface, the flagellar pocket membrane, as well as on membranes of endosomes and lysosome-like structures. These antibodies were unable to stimulate in vitro complement-mediated lysis of trypanosomes, and in an in vitro test of parasite growth inhibition they actually marginally enhanced parasite proliferation. No effect was observed on the parasite prepatent period or parasitemia in mice injected with antibody purified from the rabbit antisera, but their survival with the infection was significantly shortened. Finally, little difference was detected in parasitologic or hematologic parameters between immunized and control rabbits upon challenge with T. brucei infection.

The HLA restriction and epitope specificity of cytotoxic T lymphocytes (CTL) involved in recovery from influenza type B infection have not been extensively characterized. Here lymphocytes obtained from a healthy individual contained virus-specific CTL restricted by class I HLA molecules, HLA-A1, A2, B7 and B8, and the class II HLA molecules, HLA-DR1 and DR3. Four conserved viral epitopes were predicted from allele-specific motifs for peptides interacting with HLA-B8 and HLA-DR1. Bulk CTL recognized three 9mer HLA-B8-restricted peptides from nucleoprotein, residues 30-38, 263-271 and 413-421, and a 13mer HLA-DR1-restricted peptide from hemagglutinin, residues 308-320. The epitopes presented by HLA-A1, HLA-B7 and HLA-DR3 remain undefined. Peptide-specific CTL lines recognized influenza type B virus-infected cells indicating the peptides are representative of naturally processed epitopes. A hemagglutinin peptide-specific CD4 CTL clone expressed approximately 200 molecules of perforin mRNA/cell, suggestive of a functional perforin pathway for target cell lysis. The results indicate a broad CTL response composed of both CD8 CTL and CD4 CTL recognizing viral epitopes presented by multiple HLA molecules.

The number, type, and location of cytokine- and Ab-secreting cells activated in mice immunized and boosted with plasmid DNA encoding the circumsporozoite protein of the malarial parasite Plasmodium yoelii (PyCSP) were monitored. The initial humoral response was localized to the draining lymph nodes and was characterized by production of IgG1 anti-PyCSP Abs and the Th2 cytokine IL-4. In contrast, the secondary response was dominated by IFN-gamma production (a Th1 cytokine) and the secretion of IgG2a anti-PyCSP Abs in the spleen. PyCSP DNA and mRNA were detected only in the quadriceps muscles (sites of plasmid injection), yet these sites lacked either cytokine- or Ab-secreting cells. These findings indicate that circulating lymphocytes encounter plasmid-encoded Ag in the muscle bed, initiate a humoral response in the draining lymph nodes, and then seed distal lymphoid organs. Profound differences were observed between the primary and secondary immune responses induced by plasmid immunization, which may influence vaccine efficacy.

Evidence about screening for breast cancer demonstrates how principles of clinical epidemiology can be used to aid in decisions about clinical care and health care policy. Regardless of condition, three key questions must be asked and answered before undertaking screening: 1) How great is the burden of suffering caused by the condition? 2) How effective is early treatment following screening (as opposed to results of treatment when the condition would be diagnosed without a screening program)? and 3) How good is the screenning test in terms of sensitivity, specificity, predictive value, simplicity, cost, safety, acceptability and labeling effects? Breast cancer incidence and mortality varies by country. In the United States, breast cancer is the most common non-skin cancer and second most deadly cancer in women. There are three main tests used, either alone or in combination, for breast cancer screening: mammography, clinical breast examination by a health professional, and breast selfexamination. Mammography, with or without clinical breast examination clearly reduces mOltality in women aged 50-69, but the effect in younger women remains unclear even after trials involving approximately 170,000 women. Eight randomized controlled trials all showed mortality reductions for women over 50 years of age; at seven years of follow-up, the combined result showed a 34% mortality reduction that was statistically significant. These same studies were inconsistent in finding mortality reductions in women ages 40-49, combined analyses showed no effect at seven years of follow-up ahd a 10% to 17% statistically insignific Iant reduction at 10 to 12 years. This delayed and smaller trend in younger women may be due to the fact that many women entering trials in their forties had their cancers diagnosed when they were in their fifties, at an age when mammography is known to be effective. Only one randomized controlled trial has been done comparing mortality differences after either mammography or a very through clinical breast examination. At seven years of follow-up, there was no difference in mortality rates. No randomized trials of breast self-examination have reported mortality data. Mammography is the most sensitive screening test currently available for breast cancer screening. The high falsepositive rate of mammography can lead to substantial numbers of women experiencing anxiety about breast cancer, the possibility of overdiagnosis with "pseudocancers"is real, and the high cost of mammography in the United States means already almost $3 billion is spent annualy on mammography, about half or which is for women under age 50. When preventive policies are promulgated, strong evidence of benefit is essential because so many people must be screened to potentialy help one person. While much more needs to be done to ensure that all women aged 50-69 recei ve routine screening in countries where breast cancer on an important health risk, more research is necessary before instituting routine breast cancer screening in younger women.

Background: Numerous studies have reported differences in cancer staging at diagnosis and in survival between Black and White patients with breast cancer. Utilizing data obtained from the National Cancer Institute's (NCI's) Black/White Cancer Survival Study for the period 1985-1986, a new study is presented here that systematically examines multiple explanatory factors (e.g., lack of mammograms) associated with these cancer-staging differences. Purpose: We evaluated within a single study the relationship of selected demographic, lifestyle, antecedent medical experiences, and health care acces s factors to cancer staging at diagnosis in Black and White breast cancer patients. Methods: Data utilized in this population-based cohort study of 1222 eligible women (649 Black and 573 White) newly diagnosed for the period 1985-1986 with histologically confirmed primary breast cancer were obtained from the NCI's Black/White Cancer Survival Study. Sources of data included abstracts of hospital medical records, central review of histology slides by a study consultant pathologist, and patient interviews obtained from three metropolitan areas: Atlanta, New Orleans, and San Francisco-Oakland. Within each area, 70% of all Black incident cases were randomly selected, and a sample of White cases, frequency matched by age groups (20-49 years, 50-64 years, and 65-79 years), was selected for comparison. Stage of breast cancer at diagnosis was classified according to the international tumor-lymph node-metastases (TNM) system. Statistical models utilized in this study included the log-linear and polychotomous logistic regression with multiple predictor variables. Results: Factors associated with cancer staging were differentially expressed in Blacks and Whites. Indicators of access to health care, a lack of mammograms, and an increased body mass index significantly (P<.02) contributed to stage differences in Blacks, whereas income was marginally associated (P = .06) with stage for Whites only. Nuclear grade, having a breast examination by a physician, and a history of patient delay explained approximately 50% of the excess risk for stage III-IV Cancer versus stage I-II(N0) cancer among Blacks compared with Whites (odds ratio- reduction from 2.19 to 1.68). Conclusion: These findings suggest that no single factor or group of factors can explain more than half of the race-stage differences noted in this study with respect to Black and White breast cancer patients.

BACKGROUNDOver the past 30 years, eight major randomized controlled trials of breast cancer screening--with mammography and/or clinical breast examination--have been conducted. Results from several trials have been updated during the past year, and initial results of three other trials have been reported.PURPOSEThe National Cancer Institute held an International Workshop on Screening for Breast Cancer in February 1993 to conduct a thorough and objective critical review of the world's most recent clinical trial data on breast cancer screening, consider the new evidence, assess the current state of knowledge, and identify issues needing further research.METHODSInvestigators representing the eight randomized controlled trials of breast cancer screening in women aged 40-74 presented published and unpublished data. Evidence relating to the effectiveness of breast cancer screening in different age groups, especially women aged 40-49, was presented.RESULTSFor women aged 40-49, randomized controlled trials consistently demonstrated no benefit from screening in the first 5-7 years after study entry. A meta-analysis of six trials found a relative risk of 1.08 (95% confidence interval = 0.85-1.39) after 7 years' follow-up. After 10-12 years of follow-up, none of four trials have found a statistically significant benefit in mortality; a combined analysis of Swedish studies showed a statistically insignificant 13% decrease in mortality at 12 years. Only one trial (Health Insurance Plan) has data beyond 12 years of follow-up, and results show a 25% decrease in mortality at 10-18 years. Statistical significance of this result is disputed, however. In women aged 50-69, all studies show mortality reductions; three of four studies show reductions of about 30% at 10-12 years after study entry. Results from two of these trials were statistically significant. Too few women over age 70 have been included in studies for adequate analysis.CONCLUSIONSFor women aged 40-49, randomized controlled trials of breast cancer screening show no benefit 5-7 years after entry. At 10-12 years, benefit is uncertain and, if present, marginal; thereafter, it is unknown. For women aged 50-69, screening reduces breast cancer mortality by about a third. Currently available data for women age 70 or older are inadequate to judge the effectiveness of screening.IMPLICATIONSRandomized trials have provided stronger scientific evidence regarding the effectiveness of screening for breast cancer than for any other cancer. However, much still needs to be learned. Periodic gatherings of scientists in the field should speed the process.

Antisera from guinea pigs made resistant to infestation with an ixodid tick of east and central Africa, Rhipicephalus appendiculatus, were used to identify the tick antigens they recognized by immunoblotting. Most of the antigens were found in tick salivary glands and in tick attachment cement. Antisera from R. appendiculatus-resistant guinea pigs also recognized some salivary-gland antigens in ticks of other species (R. pulchellus, R. evertsi, Amblyomma variegatum and A. gemma). Antibodies against the most strongly recognized R. appendiculatus antigen, a 20-kDa molecule, were only poorly reactive with similar-sized molecules in the other ticks. A 94-kDa antigen, which appeared to have broader cross-reactivity, was purified from R. appendiculatus attachment cement, and a monospecific rabbit serum was raised against it. This antiserum clearly recognized a molecule of similar molecular weight in R. pulchellus and R. evertsi. Intravenous inoculation of rabbits with the purified molecule elicited delayed-type hypersensitivity to the antigen. The hypersensitive rabbits demonstrated resistance to feeding of R. appendiculatus ticks but slight enhanced feeding of R. pulchellus ticks. These results are discussed with respect to their relevance for artificial induction of tick-feeding resistance.