This blog is adapted and cross-posted from HIV.gov. 

During the first full day of presentations at the 2024 Conference on Retroviruses and Opportunistic Infections (CROI), HIV.gov spoke with Carl Dieffenbach, Ph.D., director of NIAID’s Division of AIDS, about research presented on Doxy-PEP for sexually transmitted infections (STIs) and HIV vaccines. He spoke with Louis Shackelford of the HIV Vaccine Trials Network. Watch their conversation.

Louis also spoke with LaRon Nelson, Ph.D., R.N., F.N.P., F.N.A.P., F.N.Y.A.M., F.A.A., about community-engaged research, HIV prevention at CROI, and a new study (HPTN 096) he is leading to reduce HIV rates among Black men who have sex with men (inclusive of cisgender and transgender men) in the southern United States. Dr. Nelson is a professor and the associate dean at the Yale School of Nursing. Watch their conversation.

Insights from Doxy-PEP Use in Real World Settings

At last year’s CROI, researchers presented results from an NIH-supported study on using a preventive dose of the antibiotic doxycycline as post-exposure prophylaxis within 72 hours after condomless sex to prevent bacterial STIs, an approach that has become known as Doxy-PEP. (View last year’s Doxy-PEP discussion with Dr. Dieffenbach.) Here at CROI 2024, Dr. Annie Luetkemeyer of the University of California, San Francisco, shared additional findings from the open-label extension of that original study, which found sustained reduction of bacterial STIs among men who have sex with men and transgender women living with HIV or on PrEP in Seattle and San Francisco. The San Francisco AIDS Foundation (SFAF) was one of the first organizations in the United States to roll out Doxy-PEP, beginning in late 2022 when it was offered to all active PrEP clients at their visits at the Magnet clinic. SFAF medical director Dr. Hyman Scott reported that there was high uptake among clients and that bacterial STIs decreased by nearly 60% in less than a year at SFAF’s clinic. The decline was highest for syphilis (78%) and chlamydia (67%). 

The San Francisco Department of Public Health (SFDPH) presented the first findings to measure the effect of Doxy-PEP at the population level. Their analysis, presented by epidemiologist Madeline Sankaran, showed a substantial and sustained decline in the number of chlamydia and early syphilis infections in San Francisco among men who have sex with men and transgender women over the 13 months after the Department released guidelines for the use of Doxy-PEP. As in the other studies presented, SFDPH did not see corresponding significant declines in gonorrhea. Doxy-PEP is not recommended for cis-gender women because there is not yet evidence to suggest it is effective for them.

HIV Vaccine Trials Continue

Dr. Dieffenbach also discussed ongoing research to find a vaccine to prevent HIV, the topic of several presentations at the conference so far. Since there are a number of Phase I HIV vaccine trials currently underway, he and Louis spoke about what those smaller trials do. Then they discussed what some of the HIV vaccine trials currently underway are exploring.

Other Studies of Interest Presented on Monday

Some of the other studies presented centered on broadly neutralizing antibodies (bNAbs), including bNAbs as part of HIV therapy and how different HIV variants can affect bNAb efficacy as a treatment method. A new analysis from the pivotal HVTN 083 study of long-acting PrEP with cabotegravir found no significant risk of hypertension in people using the method, which had been a concern in some previous clinical studies of the same class of antiretroviral drugs.

Community-Engaged Research

The importance and significant benefits of involving community in all aspects of HIV research was the first topic Dr. Nelson and Louis discussed. “If we don’t have community voices or engaged communities, we aren’t going to be asking the right questions or designing the studies in the best ways that will produce the outcome that we need, and we won’t end up with answers that are as relevant as they could be,” Dr. Nelson observed. He pointed to the dapivirine vaginal ring as an example of better outcomes because communities were involved in research. He said he hopes that community engagement in research continues to become more and more common, but it requires that researchers be willing to listen and, when needed, change their plans based on what they hear from community.

HIV Prevention Research at CROI

Dr. Nelson highlighted some of the HIV prevention topics at CROI that have caught his attention, such as increasing equitable use of long-acting injectable forms of HIV PrEP and treatment among different populations and in different countries. Other discussions of interest have included early studies on potentially very long-acting forms of HIV PrEP and exploration of possible dual prevention tools that would provide users with both HIV PrEP and contraception.

HPTN 096 Study

Finally, Dr. Nelson discussed an example of community-informed research that will soon be underway: the NIH-supported study through the HIV Prevention Trials Network (HPTN) known as HPTN 096. It aims to reduce HIV rates among Black men who have sex with men in the southern United States using a strategy developed based on what communities have told Dr. Nelson and colleagues is needed to do so. As a result, the study includes a package of four interventions which simultaneously address social, structural, institutional, and behavioral barriers to HIV prevention and care. HPTN 096 will soon launch in Atlanta, south Florida, Montgomery, Memphis, and Dallas.

More HIV Research Updates to Follow on HIV.gov

HIV.gov will be sharing additional video interviews from CROI 2024 with Dr. Dieffenbach, CDC’s Dr. Jono Mermin and Dr. Robyn Neblett Fanfair, and others. You can find all of them on HIV.gov’s social media channels and recapped here on the blog.

A messenger RNA (mRNA) vaccine designed to prevent human cytomegalovirus (CMV) elicited long-lasting CMV-specific responses from several types of immune cells, outperforming a previous vaccine concept in multiple measures in a NIAID-supported laboratory study. The findings were published in the Journal of Infectious Diseases.

CMV has been present in much of the global population for centuries. Most people with CMV experience no symptoms and are unaware that they are living with the virus, but CMV is dangerous for people with compromised immune systems and for babies. It is the most common infectious cause of birth defects in the United States. When babies acquire CMV through birth it is called congenital CMV, and it affects about 1 out of every 200 children. Of babies with CMV, about 1 in 5 will experience long-term health effects, including hearing or vision loss, developmental and motor delays, seizures, or microcephaly (a small head). Infants born before 30 weeks’ gestational age or with low weight for age that have CMV may be susceptible to additional complications.

There is no preventive vaccine for CMV, and treatment options are limited. An effective CMV vaccine could present needless suffering for millions of babies, and research has been progressing for decades. A recent vaccine candidate was designed to use a laboratory-developed protein from CMV’s surface called glycoprotein B (gB)—known to assist CMV in fusing with and entering human cells—to safely teach the immune system how to respond to CMV exposure without causing disease. The vaccine provided about 50% protection from CMV in Phase 2 trials, but that effect was insufficient for the concept to advance to large efficacy studies. 

A different, mRNA-based, vaccine is now in a Phase 3 efficacy study in cisgender women with no existing CMV infection. The vaccine was designed to instruct cells to produce the gB protein while also producing a combination of five other glycoproteins on CMV’s surface, which like gB are involved in human cell entry.

To better understand how the mRNA vaccine might perform in comparison to gB-based vaccine, researchers examined the immune cells present in blood samples provided by people when they participated in previous studies of each vaccine. The study team performed several assays—laboratory tests—and made the following key observations:

• The mRNA vaccine generated higher levels of antibodies to the five glycoproteins unique to the that vaccine in the form of immunoglobulin G (IgG) antibodies, which are associated with long-term immunity.
• The mRNA vaccine generated more potent signals that the immune system was prepared to deploy antibodies to surround and neutralize—destroy—CMV.
• The gB-based vaccine generated higher levels of IgG antibodies to gB.
• Immune responses to both vaccines were greater in study participants with no existing CMV, but the vaccines still amplified immune system activity in people already living with the virus. 

The authors concluded that the mRNA vaccine concept showed promise for better performance than its predecessor in ongoing clinical studies, of which results are expected soon. These results also highlight an opportunity to reformulate the mRNA vaccine to increase the amount of gB proteins it generates, which in tun could improve gB-specific immune responses.

This work was led by Weill Cornell Medicine in collaboration with the Duke Human Vaccine Institute at Duke University Medical Center, Vanderbilt University, Cincinnati Children’s Hospital Medical Center, and Moderna, Inc. in Cambridge, Mass. Moderna co-funded the research with NIAID.

Reference: X Hu, et al. Human Cytomegalovirus mRNA-1647 Vaccine Candidate Elicits Potent and Broad Neutralization and Higher Antibody-Dependent Cellular Cytotoxicity Responses Than the gB/MF59 Vaccine. Journal of Infectious Diseases DOI: 10.1093/infdis/jiad593 (2024). 

World Neglected Tropical Diseases (NTD) Day offers an opportunity to reflect on recent strides in tropical disease research and the work that remains. NIAID conducts and supports work on a wide variety of diseases—some of which rarely make headlines but cause immense suffering. An example of this is leishmaniasis, a parasitic disease that sickens hundreds of thousands of people each year, mostly in equatorial regions of the globe. In recent years, NIAID has made significant efforts to study the parasite that causes the disease and find new ways to battle it.

The single-celled Leishmania parasite, which is spread by the bites of infected sand flies, can cause a wide array of symptoms. Cutaneous leishmaniasis, the most common form of the disease, is a skin infection.  It manifests as skin ulcers, which may lead to lifelong scarring. The World Health Organization estimates that between 600,000 and 1 million people get cutaneous leishmaniasis each year. A rarer form, mucosal leishmaniasis, attacks the membranes in the nose and mouth and results in painful ulcers, nosebleeds, and related symptoms.

The most severe form is visceral leishmaniasis (also known as kala-azar), in which the Leishmania parasites attack the patient’s internal organs, such as the spleen, liver and bone marrow. This leads to organ dysfunction that is usually fatal if left untreated. Sick patients with visceral leishmaniasis often have fevers, anemia, weight loss and severe fatigue. While a wide array of therapeutics can be used to treat leishmaniasis, not all therapeutics work equally well for different forms of Leishmania parasites.

This diversity of treatment options poses a serious problem for healthcare providers because there are at least 20 species of Leishmania. Studying each individual strain and how they differ from one another will be key in developing therapeutics and preventive measures. NIAID supports a Tropical Medicine Research Center (TMRC) in Sri Lanka, which has conducted epidemiological and molecular studies on locally occurring types of Leishmania, comparing it with strains from India.

Unfortunately, recent research has suggested that different strains of Leishmania are capable of hybridizing with each other, potentially creating offspring resistant to multiple kinds of drugs. How this occurs is largely a mystery, given that Leishmania are single-celled protozoa, and when observed in the lab setting, largely reproduce by cloning themselves. A recent paper from researchers at NIAID explores how their hybridization works. By analyzing the whole genomes of Leishmania parasites, the researchers identified several genes which could allow the parasites to perform meiosis-like gene recombination. In other words, they have the necessary genes to perform a genetic recombination and exchange process similar to sexual reproduction in animals and plants. Understanding how these hybrids arise could be key to understanding how the different strains evolve and change in the future.

To better prepare for these changes, other NIAID-supported researchers are investigating new therapeutics for leishmaniasis and finding better uses for existing therapeutics. In 2021, a team investigating oral antifungal agents for leishmaniasis found that a miltefosine/posaconazole combination worked well together ex vivo, and could be very effective against the most common Leishmania species in Colombia. This year, a different group of scientists found a new therapeutic agent that seems to harm several different species of Leishmania parasites during the part of their life cycle when they are infecting human cells. This agent could be, in theory, both easy and cheap to produce, making it an appealing prospect as a treatment if proven safe and effective in later studies. A third group with NIAID support has been doing early work to optimize a series of imidazopyridine drugs, which pharmacokinetic surveys hint might be effective against visceral Leishmania species. This process attempts to increase the agent’s potency against Leishmania while also making it more tolerable for mammalian cells.  

As with many neglected tropical diseases, researching the parasite’s vector is also key to understanding this disease. The sand flies that carry the Leishmania parasite are tiny—smaller than mosquitoes—and transmit the parasites when they bite people and take a blood meal. Another NIAID TMRC, based in East Africa, conducts research on the ecology and behavior of sand flies, in the hopes of finding ways to control the disease by controlling the flies. In the United States, NIAID supports the Sand Fly Repository at the Walter Reed Army Institute of Research, the largest sand fly repository in the world. Through the repository, researchers can access flies from 15 different colonies for use in their own work.

Leishmaniasis remains challenging to prevent and treat—and like all neglected tropical diseases, its impact on people in affected areas is significant. NIAID’s efforts to study Leishmania and its hosts will continue in the years to come in the hopes of finding new and improved ways to combat this disease

NIAID Approach Highlighted in New Journal Supplement

A special Oct. 19 supplement to the Journal of Infectious Diseases contains nine articles intended as a summary of a National Institute of Allergy and Infectious Diseases (NIAID)-hosted pandemic preparedness workshop that featured scientific experts on viral families of pandemic concern. Sponsored by NIAID, the supplement features articles on 10 viral families with high pandemic potential known to infect people. Concluding the supplement is a commentary from NIAID staff on the “road ahead.”

Many of the viruses in these 10 families have no vaccines or treatments licensed or in advanced development for use in people. Rather than facing the enormous task of developing medical countermeasures for individual viruses, one strategy is to use the “prototype pathogen” approach – which was shown to be successful with the rapid development of vaccines during the SARS-CoV-2 pandemic. This approach characterizes “representative” viruses within viral families so that knowledge gained, including medical countermeasures strategies, can be quickly adapted to other viruses in the same family.

The NIAID workshop on pandemic preparedness had several goals, including to describe the prototype pathogen approach, select prototype pathogens for future study, and identify knowledge gaps within the selected viral families. Prototype viruses being considered for study within the 10 families of pandemic concern are listed below. The ranges of these prototype viruses span the globe.

• Arenaviridae: These viruses are capable of spillover from animals to people and can lead to severe viral hemorrhagic fevers. Lassa virus and Junín virus were selected as prototypes.
• Bunyavirales, includes the Hantaviridae, Nairoviridae, Peribunyaviridae and Phenuivirdae families, among others. Viruses in this family are spread by several different arthropods (mosquitoes, ticks, midges) or rodents and can cause mild to severe symptoms and death.
  • Phenuivirdae prototypes are Rift Valley fever virus, severe fever with thrombocytopenia syndrome virus (SFTSV), Toscana virus, and Punta Toro virus.
  • Nairoviridae prototypes are Crimean-Congo hemorrhagic fever virus and Hazara virus.
  • Hantaviridae prototypes are Hantaan virus, Sin Nombre virus, and Andes virus.
  • Peribunyaviridae prototypes are La Crosse virus, Oropouche virus, and Cache Valley virus.
• Paramyxoviridae: This family includes highly transmissible viruses that are well known (measles, mumps) and more recently emerged (Nipah virus). Viruses proposed as prototypes are Cedar virus, canine distemper virus, human parainfluenza virus 1/3, and Menangle virus.
• Flaviviridae: These viruses, primarily transmitted by mosquitoes and ticks, are responsible for hundreds of millions of human infections worldwide each year. Viruses proposed as prototypes are West Nile virus, dengue serotype 2 virus, and tick-borne encephalitis virus.
• Togaviridae: Most of these viruses are spread by mosquitoes and cause disease in animals that then can spillover to people. Viruses proposed as prototypes are Chikungunya virus and Venezuelan equine encephalitis virus.
• Picornaviridae: This family includes common human viruses such as polio and hepatitis A, but new technology has led scientists to recently discover more than 300 new viruses. The four selected prototypes are enteroviruses A71 and D68, human rhinovirus C virus, and echovirus 29.
• Filoviridae: Filoviruses can cause severe hemorrhagic fever in people and have been causative agents of recent outbreaks. Ebola virus is the prototype virus.

Experts with careers built on knowledge of each virus family are leading research teams across the U.S., studying how viruses infect cells, which models of disease most closely mimic human disease, and how to use new technology when designing vaccines and treatments. NIAID leaders are anticipating that the prototype approach will create “opportunities for investigators from multiple fields or with specialized technical expertise to collaborate in new ways.”

Reference: Pandemic Preparedness at NIAID: Prototype Pathogen Approach to Accelerate Medical Countermeasures—Vaccines and Monoclonal Antibodies. Journal of Infectious Diseases (2023).

Following a peak in the summer of 2022, new infections in the mpox clade IIb outbreak have decreased, due in part to the rapid availability and uptake of vaccines and other preventive measures. However, mpox remains a health threat, and no treatment has been proven safe and effective for people experiencing mpox disease.

The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, launched the STOMP trial to determine whether the antiviral drug tecovirimat can safely and effectively treat mpox. Tecovirimat, also known as TPOXX, was initially developed and approved by the Food and Drug Administration to treat smallpox—a species of virus closely related to mpox—but the drug’s safety and efficacy as an mpox treatment has not been established. The STOMP trial is a phase 3 study that aims to enroll about 500 people—a process that may require considerable time while mpox burden is low in study countries. NIAID continues to prioritize this study even while case counts are low.

VIDEO: Cyrus Javan of NIAID’s Division of AIDS explains the importance of the STOMP trial (audio description version here):

The STOMP trial was designed to be as inclusive as possible to ensure study results provide information on how tecovirimat works in the diverse populations affected by mpox. The trial is enrolling adults and children of all races and sexes, people with HIV, and pregnant and lactating people across 60 sites in the United States and Mexico, with an option for remote enrollment from other U.S. locations. More sites are expected to open in East Asia and South America.

The mpox virus has been endemic—occurring regularly—in west, central and east Africa since the first case of human mpox disease was identified in 1970. Mpox can cause flu-like symptoms and painful blisters or sores on the skin. People who acquire mpox tend to clear the infection on their own, but the virus can cause serious disease in children, pregnant people, and other people with compromised immune systems, including individuals with advanced HIV disease. Rare but serious complications of mpox include dehydration, bacterial infections, pneumonia, brain inflammation, sepsis, eye infections and death.

Completing the STOMP trial is essential, not only to evaluate a therapeutic option for the current mpox outbreak, but also to guide preparation for future outbreaks and provide evidence that could inform medical practice in historically endemic countries. The STOMP trial is sponsored by NIAID and led by the NIAID-funded Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG).

Beyond STOMP, NIAID is co-sponsoring the PALM007 trial of tecovirimat as treatment for clade I mpox in the Democratic Republic of the Congo (DRC) with the DRC’s National Institute of Biomedical Research. PALM007 is actively enrolling. In addition, NIAID is sponsoring an immunogenicity study of the JYNNEOS preventive vaccine, which has completed enrollment and is expected to report initial results in 2024. More information about these studies, including enrollment in STOMP and PALM007, is available here:

STOMP tecovirimat treatment study 
PALM007 tecovirimat treatment study
JYNNEOS vaccine study