An HIV vaccine candidate elicited trace levels of HIV broadly neutralizing antibodies (bNAbs) and high levels of other key immune cells in an early-stage clinical trial. This immune response is an important signal that, if antibody levels can be further amplified, the vaccination strategy might be able to prevent HIV. The findings of this NIAID-supported trial were published in the journal Cell.

HIV has genetic diversity that makes it difficult to target with a vaccine, but bNAbs are thought to be key to overcoming that hurdle because they bind to parts of the virus that remain relatively stable even when it mutates. Several classes of HIV-specific bNAbs have been identified, and each class binds to a different stable section of the virus’ surface. Some people with HIV generate bNAbs naturally through a process that typically occurs over years. For a preventive vaccine, researchers seek to accelerate the process by which the immune system generates bNAbs and to do so in people who do not have HIV. 

The clinical trial examined the ability of a vaccine concept to elicit bNAbs that bind to the membrane proximal external region (MPER) of an HIV surface protein. The study enrolled 24 participants, of whom 20 were randomly selected to receive vaccine doses. The remaining four participants received placebo injections. Fifteen participants in the vaccine arm received two doses, and five participants received three doses. The team then analyzed study participant blood samples. 

They found that 13 vaccine recipients generated early-stage MPER-directed antibodies after two doses. Among the five participants who received three doses, the antibodies in samples from two of them could neutralize many common globally circulating HIV strains in vitro, i.e., in a test tube or culture dish. One of those two participants had B cells—immune cells that produce antibodies—showing signs of maturing in such a way that they would be able to produce MPER-directed bNAbs if stimulated further. The other participant had started producing MPER-directed bNAbs. Vaccine recipients also had evidence of CD4+ T cell activity, which is a crucial step in enabling antibody development. One vaccine recipient experienced anaphylaxis, a known but rare allergy-related adverse event, which was promptly managed and resolved. The team investigated the cause of the event, which was likely from an additive used to help stabilize the vaccine contents. The trial was halted at that time.  

The research was sponsored by NIAID, co-funded by the Bill & Melinda Gates Foundation, and conducted by the Duke Consortium for HIV/AIDS Vaccine Development (CHAVD), one of two NIAID-supported HIV vaccine consortia, in collaboration with the NIAID-funded HIV Vaccine Trials Network. This study provided the proof of concept that a vaccine can induce bNAbs in people, which is a key question being pursued in the HIV vaccine research field. Moreover, bNAbs were detected within weeks, which is much faster than the antibody response in people with HIV. According to the authors, it is likely that an effective vaccine will need to build on and amplify the immune response that was observed in this study. Together, the clinical trial results identified ways that the vaccine’s safety and efficacy must be enhanced before it advances through further evaluation, and a new vaccine candidate is being developed based on these findings.

NIAID is grateful to the research teams and volunteers who participate in HIV vaccine studies. 

For more information about this study, please visit ClinicalTrials.gov and use the study identifier NCT03934541.

Reference 

W Williams et al. Vaccine induction of heterologous HIV-1-neutralizing antibody B cell lineages in humans. Cell DOI: 10.1016/j.cell.2024.04.033 (2024)

Vaccines consistently transform public health, and HIV vaccine research has been a pillar of NIAID’s scientific mission since the beginning of the HIV pandemic. An HIV vaccine has proven to be among the most daunting scientific challenges, but has inspired exceptional innovation and collaboration in all aspects of our research approach. On the 27th observance of HIV Vaccine Awareness Day (Saturday, May 18), we express our gratitude to the dedicated global community of scientists, advocates, study participants, study staff, and funders working toward a safe, effective, durable, and accessible HIV vaccine. 

As the lead of the National Institutes of Health HIV vaccine research effort, NIAID conducts basic, preclinical, and clinical research to characterize the safety, immunogenicity, and efficacy of promising HIV vaccine concepts. Through the HIV Vaccine Trials Network, NIAID supports clinical trials where HIV is most prevalent, including in the Global South. Over decades of research, with disappointing results from large efficacy studies, the HIV vaccine field has learned and iteratively evolved with every step. We have more knowledge now than ever before about how an HIV vaccine could work. Research teams are using discovery medicine trials and new vaccine technologies to identify and stimulate the types of immune responses that hold the most promise for preventing HIV.   

People with HIV have made priceless contributions to HIV vaccine science by participating in research that teaches us how the human immune system responds to HIV. Some people naturally keep the virus under control even without antiretroviral therapy. Through their participation in clinical research, we have identified aspects of both cellular immunity—which is driven by T cells—and humoral immunity—driven by antibody-producing B cells—that likely will need to be stimulated and substantially amplified by a safe and effective preventive vaccine. 

HIV’s genetic diversity makes it difficult to target with a vaccine, but broadly neutralizing antibodies (bNAbs) may be key to overcoming that hurdle because they bind to parts of the virus that are relatively consistent among variants. The NIAID Vaccine Research Center (VRC)—founded to accelerate HIV vaccine research on this day in 1997—isolated and then manufactured a bNAb called VRC01 that has prompted a cascade of other research, including HIV vaccine and passive antibody administration studies. 

Since the VRC’s discovery of VRC01, scientists have identified additional bNAbs that target other stable sites on HIV’s highly variable surface. This year, VRC scientists showed that a human bNAb called VRC34.01, which targets the fusion peptide on HIV’s surface, protected monkeys from acquiring simian-HIV in a proof-of-concept study that is informing human vaccine design. Researchers at the VRC and other NIAID-supported institutions are using a technique called germline targeting to closely guide naïve (new) B cells to develop into mature B cells that can produce bNAbs. Using this approach, researchers are making progress toward eliciting VRC01-like antibodies, as well as several other classes of bNAbs in human and animal studies.

Researchers also are advancing cellular immune approaches to HIV vaccines. A study conducted by NIAID’s Laboratory of Immunoregulation found that a safe and effective HIV vaccine will likely need to stimulate strong responses from CD8+ T cells. NIAID and its partners announced the launch of a clinical trial to examine the safety and immune response generated by VIR-1388, a T-cell based vaccine candidate that uses a cytomegalovirus (CMV) vector.  In this approach, a weakened version of CMV delivers HIV vaccine material to the immune system without causing disease in the study participants. The CMV vector technology has been in development with NIAID funding since 2004. 

We also are reminded how HIV vaccine research and discovery benefits the broader fields of immunology and vaccinology. In October 2023, the Nobel Prize for Physiology or Medicine was awarded to Drew Weissman, M.D., Ph.D., and Katalin Karikó, Ph.D., for their work that enabled the unprecedented rapid development of the mRNA vaccines that stemmed the COVID-19 pandemic and saved millions of lives. Both Nobel laureates have connections to NIAID and NIH. This research was made possible in part by NIAID HIV vaccine research grants that enabled a major evolution in understanding how immune cells recognize and react to different forms of mRNA. mRNA-based HIV vaccine candidates are now being tested in humans in early-stage trials.

Looking ahead, NIAID has clear priorities for HIV vaccine research and development. Ongoing research is guiding the next steps in vaccine strategies to elicit bNAbs and T-cell responses, to eventually trigger both with a single vaccine regimen. To enhance the precision of this research, more information is needed to define the correlates of protection for an HIV vaccine, that is, the specific immunologic markers that translate to a protective effect. Meanwhile, as promising concepts are identified and advanced through clinical trials, the field must continue to optimize vaccine formulations and dosing, and find novel adjuvants that can prolong and amplify immune responses. HIV vaccine research findings will continue to offer valuable insight in other areas, including HIV prevention and cure research, and broader medical countermeasure development for pandemic preparedness.

The pursuit of an HIV vaccine depends on supporting next the generation of HIV clinical investigators and community leaders. NIAID is committed to fostering the professional growth of early-stage HIV investigators and to nurturing the decades-long community partnerships that make this essential research possible.  

On this HIV Vaccine Awareness Day, we remain optimistic that exciting scientific advances and the efforts of diverse partners around the world will put a safe and effective HIV vaccine within our grasp.

A preventive vaccine for gonorrhea would be a major advance in public health, according to an editorial co-authored by NIAID Director Jeanne Marrazzo, M.D., M.P.H, and Myron Cohen, M.D., director of the Institute for Global Health and Infectious Diseases at the University of North Carolina at Chapel Hill. The editorial, published in the Journal of Infectious Diseases, provides context on new mathematical modeling projecting the cost-effectiveness of the meningitis B vaccine 4CMenB, which is currently being evaluated as a preventive intervention for gonorrhea. 

Gonorrhea, a common sexually transmitted infection, afflicts more than 80 million adults each year, according to the World Health Organization. It is caused by the Neisseria gonorrhoea bacterium. Untreated gonorrhea can lead to serious and permanent health conditions, such as pelvic inflammatory disease, painful swelling and blockages in male reproductive organs, and infertility. While usually treatable with antibiotics, N. gonorrhoeae bacteria have demonstrated resistance to most existing classes of antibiotics. The genetic sequences of N. gonorrhoeae and Neisseria meningitidis group B, the bacteria that can cause meningitis B, are closely related, which have led researchers to explore whether the 4CMenB vaccine, approved by the Food and Drug Administration for meningitis B, might also prevent gonorrhea. 

NIAID is sponsoring an efficacy study of the 4CMenB vaccine for gonorrhea prevention in more than 2,000 people aged 18-50 years in Malawi, Thailand, and the United States. The Kirby Institute is studying the same vaccine among gay, bisexual, and other men who have sex with men in Australia, and GlaxoSmithKline is studying a vaccine specifically designed to prevent gonorrhea, to assess its safety and potential efficacy. All studies are expected to report results within the next two years. 

The mathematical modeling published with the editorial was led by Imperial College London with funding through the Global Health EDCTP3 Joint Undertaking and the UK Health Security Agency. The model projected how the dosing, vaccine effectiveness, health promotion, and availability for those most likely to benefit could affect the cost effectiveness of 4CMenB vaccination for gonorrhea, showing a potential benefit even if efficacy is low in forthcoming study results. Models will be able to generate a more accurate cost-effectiveness estimate once efficacy studies are complete.

References

MS Cohen et al. What if We Had a Vaccine that Prevents Neisseria gonorrhoeae? Journal of Infectious Diseases DOI: 10.1093/infdis/jiae160 (2024)

D Nikitin et al. Cost-effectiveness of 4CMenB Vaccination Against Gonorrhea: Importance of Dosing Schedule, Vaccine Sentiment, Targeting Strategy, and Duration of Protection. Journal of Infectious Diseases DOI: 10.1093/infdis/jiae123 (2024)

Nearly 25 million people in the United States have asthma, including 4.7 million children and adolescents. Almost 10 percent of these individuals had one or more asthma attacks within the past 12 months. Asthma can cause coughing, wheezing, chest tightness, and shortness of breath. In severe cases, breathing becomes extremely difficult. Worsening asthma can lead to missed time at school and work, emergency room visits, and even death.

Today on World Asthma Day, NIAID reaffirms its commitment to reducing illness from this chronic lung syndrome and improving quality of life for people with asthma through research that informs the development of new asthma prevention and treatment strategies. NIAID-funded studies in children and adolescents recently uncovered new risk factors for asthma and a previously unreported cause of frequent, severe asthma attacks. In addition, two new NIAID-supported studies aim to further asthma therapeutics development by shedding light on the behavior of airway-cell genes and proteins involved in regulating asthma severity and by defining poorly understood causes of airway inflammation in underserved youth with the disorder. Learn more about these recent research highlights below.

Asthma Risk Factors 

Nearly a third of infants who are hospitalized with a severe form of a common childhood lung infection called bronchiolitis develop asthma later in childhood. Predicting which infants with severe bronchiolitis are at highest risk for asthma, understanding why, and developing effective interventions remain challenges. Investigators from the NIAID-supported 35th Multicenter Airway Research Collaboration (MARC-35) recently identified genetic factors that may underlie the bronchiolitis–asthma link.

• Environmental exposures such as tobacco smoke are known to modify the function of certain genes in people, potentially resulting in long-term health effects. In one study, MARC-35 researchers examined such modifications by analyzing DNA in nasal swabs from 625 infants hospitalized with bronchiolitis. The scientists found that the genomes of some infants with severe bronchiolitis had modifications potentially caused by environmental exposures in the uterus or after birth, and these changes were associated with increased risk for asthma later in childhood. Now investigators want to identify which exposures had this detrimental effect.
• In a second study, MARC-35 researchers focused on small molecules called microRNAs, which derive from DNA and help control the genetic information that directs the building of proteins. The scientists analyzed microRNAs in nasal-swab DNA from 575 children who were hospitalized with bronchiolitis in infancy and followed until 6 years of age. The investigators identified 23 microRNAs that were turned on or off to different extents in the children who developed asthma by age 6 compared to those who did not. Now scientists want to identify what is triggering these differences and how to block them to reduce asthma risk.

Other investigators from the NIAID-funded Urban Environment and Childhood Asthma (URECA) study linked the composition of all the microbes found in the nose—the nasal microbiota—at age 3 years to respiratory health profiles ranging from high to low risk for developing asthma by age 7 years. The scientists also found that both exposure to certain microbes in house dust during infancy and a genetic predisposition to developing allergic diseases later in childhood influence how the airway microbiota develops. 

Therapeutic Insights

Scientists in NIAID’s Laboratory of Allergic Diseases recently demonstrated that a protein called RSG4 in smooth muscle cells of airway walls affects asthma severity in part by regulating airway inflammation independent of so-called G proteins. This finding builds on the lab’s 2020 discovery that blocking RSG4 in a mouse model of asthma reduced a key feature of the disease called airway hyper-responsiveness. This is a heightened sensitivity to molecules that activate smooth muscle cells in airway walls, leading to excessive airway constriction. Together the findings suggest that RSG4 in these cells could be a therapeutic target for asthma.

NIAID-supported researchers discovered recently that structural changes to nerve-cell networks in upper-airway tissues underlie asthma attacks in children who are hospitalized due to these attacks more than once a year. This contrasts with asthma attacks in children who are hospitalized less frequently, as those attacks are characterized by immune-system activity like allergic inflammation and responses to infections. The new findings, reported by the Ohio site in the NIAID-funded Childhood Asthma in Urban Settings (CAUSE) network, suggest that preventing and treating frequent severe asthma attacks in children may require an untraditional approach that targets the nervous system.

The CAUSE network also launched a new study in April 2024 to improve understanding of how airway inflammation influences asthma severity at a cellular and molecular level in children and adolescents who live in low-income urban communities. Airway inflammation in asthma may be categorized as related to a “type 2” immune response, which also plays a role in allergic diseases, or a non-type 2 immune response. The new study aims to define the cellular and molecular mechanisms associated with each type of airway inflammation in severe asthma to identify potential targets for new therapies.

NIAID thanks the hundreds of study participants and their caregivers who made these research advances possible and who help scientists continue to illuminate the complex and varied nature of asthma to reduce the burden of this disease.

by Jeanne Marrazzo, M.D., M.P.H., NIAID Director

The HIV research community is led by scientists with deep personal commitments to improving the lives of people with and affected by HIV. Some researchers, like me, have pursued this cause since the start of the HIV pandemic, growing our careers studying HIV from basic to implementation science. Our collective decades of work have generated HIV testing, prevention and treatment options beyond what we could have imagined in the 1980s. Those advances enable NIAID to explore new frontiers: expanding HIV prevention and treatment modalities, increasing understanding of the interplay between HIV and other infectious and non-communicable diseases, optimizing choice and convenience, and building on the ever-growing knowledge base that we need to develop a preventive vaccine and cure. The next generation of leaders will bring these concepts to fruition, and we need to welcome and support them into the complex and competitive field of HIV science.

Click below for a video in which NIAID grantees and I discuss the value and experience of early-stage HIV investigators (the audio described version is here):

NIAID wants to fund more new HIV scientists and we have special programs and funding approaches to meet that goal. This week, the NIH Office of AIDS Research will host a virtual workshop on early-career HIV investigators tomorrow, April 24, and NIAID will host its next grant writing Webinars in May, June, and July.

For more information about programs and support for new and early-stage investigators as well as people starting to implement their first independent grant, visit these NIAID and NIH resources: 

Information for New Investigators (NIAID)

HIV/AIDS Information for Researchers (NIAID)

OAR Early Career Investigator Resources (NIH)

Resources of Interest to Early-Stage Investigators (NIH)

Early Career Reviewer Program (NIH)