A NIAID research team has developed an additional nonhuman primate study model for Crimean-Congo hemorrhagic fever (CCHF), providing an alternative for development of critically needed vaccines and therapeutics. They hope the effort, described in a new study published in npj Vaccines, will lead to a widely available replicating RNA-based vaccine that they are testing against CCHF. In some outbreaks CCHF has had a case fatality rate up to 40%.

Cynomolgus macaques (CM), which typically develop mild to moderate CCHF disease, are the preferred model available to study how the virus causes infection and disease in people. During the COVID-19 pandemic, however, CMs were prioritized for other research, and scientists at NIAID’s Rocky Mountain Laboratories (RML) sought to develop an alternative model using rhesus macaques (RM) to continue promising pre-clinical work on a CCHF vaccine.

CCHF virus primarily is spread by Hyalomma ticks throughout Africa, the Middle East, Asia and parts of Europe. The disease, first described in 1944, infects up to 15,000 people annually, according to the World Health Organization. About 1 in 8 of those who are infected develop severe disease, which leads to about 500 deaths each year. A vaccine developed in 1974 in Bulgaria is available in some places but has not been approved by the U.S. Food and Drug Administration or the European Medicines Agency. The World Health Organization lists CCHF virus as a priority pathogen for development of vaccines.

The RML group in Hamilton, Montana, has worked with University of Washington and HDT Bio collaborators in Seattle for about 6 years on developing and evaluating the replicating RNA vaccine platform for SARS-CoV-2 and CCHFV. A collaboration between NIAID, HDT Bio and the University of Texas Medical Branch was recently awarded more than $80 million dollars in funding by the Department of Defense to advance the replicating RNA vaccine for CCHFV and Nipah virus into human clinical trials.

The researchers decided to try and adapt their CM study model to infect RMs. CMs and RMs are the two most commonly used research animals among the 22 different macaque species. RMs infected with CCHFV developed mild-to-moderate disease, similar to the CM model and consistent with mild-to-moderate disease in humans. 

The scientists then used a prime-boost schedule to show that the experimental vaccine provided six infected RMs with a protective immune response that controlled CCHF virus. The results are consistent with their findings using CMs and support continued advancement of this vaccine into human trials.

Future work with the vaccine is planned to try and pinpoint how it triggers immune responses in the animals and provides protection from CCHF virus infection. They also plan to explore which animal models will most accurately predict how the vaccine might act in people.

References:

D Hawman, et al. A replicating RNA vaccine confers protection in a rhesus macaque model of Crimean-Congo hemorrhagic fever. npj Vaccines DOI: 10.1038/s41541-024-00887-z (2024).

S Leventhal, et al. Replicating RNA vaccination elicits an unexpected immune response that efficiently protects mice against lethal Crimean-Congo hemorrhagic fever virus challenge. eBio Medicine DOI: https://doi.org/10.1016/j.ebiom.2022.104188 (2022).

E Haddock, et al. A cynomolgus macaque model for Crimean–Congo haemorrhagic fever. Nature Microbiology DOI: 10.1038/s41564-018-0141-7 (2018).

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)

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)