Universal Influenza Candidate Vaccine Performs Well in Phase 1 Trial
mRNA Version of NIAID Vaccine Begins Similar Testing 

Scientists at NIAID’s Vaccine Research Center (VRC) report in two new studies that an experimental influenza vaccine, designed to elicit immunity against a broad range of influenza viruses, performed well in a small trial of volunteers. In fact, the vaccine has advanced to a second trial led by scientists at Duke University through NIAID’s Collaborative Influenza Vaccine Innovation Centers (CIVICs).

In a phase 1 clinical trial of 52 volunteers, the vaccine developed by the VRC – known as H1ssF (influenza H1 hemagglutinin stabilized stem ferritin nanoparticle vaccine) – was safe, well-tolerated, and induced broad antibody responses that target the hemagglutinin stem. The two new studies assessing the nanoparticle vaccine published April 19 in Science Translational Medicine.

Healthy volunteers ages 18-70 enrolled at the NIH’s Clinical Center and were given either a single 20-microgram dose or two 60-microgram vaccine doses. Boosters were given 16 weeks after the initial dose. The trial enrolled between April 1, 2019, and March 9, 2020. 

Trial participants did not experience any severe adverse events; the most common vaccine reactions included mild headache, tenderness at the vaccine site, and temporary general discomfort.

As anticipated based on preclinical study results, H1ssF generated binding antibodies to the stem of the influenza H1 hemagglutinin (HA) protein. Antibody responses were observed regardless of dose or participant age. “These responses were durable, with neutralizing antibodies observed over one year after vaccination,” the authors stated, suggesting this vaccine prototype can advance further universal influenza vaccine development.

The H1ssF vaccine using an mRNA delivery system also began testing in a phase 1 clinical trial being overseen by scientists at the Duke Human Vaccine Institute, a part of NIAID’s CIVICs network. 

HA is composed of head and stem domains and enables the influenza virus to attach and enter a human cell. The immune system can mount an immune response to HA, but most of the response is directed toward the head. Influenza vaccines must be updated each year because the HA head constantly changes – a phenomenon called “antigenic drift.” The new vaccine candidate consists only of the HA stem. The stem is more conserved than the head between influenza strains and subtypes, and thus is less likely to change every season. Scientists predict that targeting the HA stem without the distraction of the HA head could induce stronger and longer-lasting immunity.

Influenza A viral HA can be divided into groups 1 and 2, and further subdivided into multiple subtypes based on their sequences. Scientists used the stem of an HA from a group 1 influenza virus to create the nanoparticle vaccine. Both group 1 and group 2 influenza viruses are among those responsible for seasonal influenza as well as the sporadic and deadly outbreaks of avian influenza viruses with pandemic potential. The H1ssF vaccine elicited responses that broadly neutralized group 1 influenza A viruses. Additional clinical trials are underway to test a ferritin nanoparticle-based vaccine designed to elicit group 2 influenza A viruses, and to test the H1ssF and the group 2 vaccine together in a cocktail aimed at approaching universal influenza vaccine coverage.

The H1ssF vaccine is unique in that it only displays the stem part of the influenza HA protein on the surface of a nanoparticle made of nonhuman ferritin. Ferritin spontaneously self-assembles into an eight-sided nanoparticle. When designed to display a part of the HA protein, the ferritin-HA proteins form particles displaying HA spikes on their surface, mimicking the natural organization of HA on the influenza virus. Displaying influenza HA surface proteins on the outside of the nanoparticle makes them easily accessible to immune cells that encounter the nanoparticle. The immune system can then learn to develop antibodies against displayed proteins. 

References:
A Widge, et al. An Influenza Hemagglutinin Stem Nanoparticle 1 Vaccine Induces Cross
Group 1 Neutralizing Antibodies in Healthy Adults. Science Translational Medicine DOI: 10.1126/scitranslmed.ade4790 (2023).

S Andrews, et al. An Influenza H1 Hemagglutinin Stem-Only Immunogen Elicits a Broadly Cross-Reactive B Cell Response in Humans. Science Translational Medicine DOI: 10.1126/scitranslmed.ade4976 (2023).

ClinicalTrials.gov search identifier NCT03814720.

As the latest research on HIV and other infectious diseases continued to be presented at the 2023 Conference on Retroviruses and Opportunistic Infections (CROI), HIV.gov spoke with Dr. Carl Dieffenbach about some of the highlights. Dr. Dieffenbach is the Director of the Division of AIDS at NIH’s National Institute of Allergy and Infectious Disease. He shared updates about some research on long-acting HIV prevention and treatment and COVID treatment and prevention. He also discussed news of another reported case of HIV cure. Watch our conversation with Dr. Dieffenbach below:

Long-Acting HIV Prevention and Treatment

Dr. Dieffenbach highlighted three NIH-supported studies that focused on the effectiveness of long-acting HIV prevention in specific populations and a demonstration of how long-acting HIV treatment can be used to reach people with multiple challenges to treatment adherence. First, he discussed a study presented by Dr. Hyman Scott of the San Francisco Department of Public Health that demonstrated the safety and effectiveness of long-acting injectable cabotegravir (CAB-LA) for HIV pre-exposure prophylaxis (PrEP) among Black men who have sex with men and transgender women who have sex with men, concluding that CAB-LA can be a powerful HIV prevention tool to reduce HIV incidence among these groups that are disproportionately affected by HIV. Next, Dr. Dieffenbach highlighted a study presented by Dr. Sybil Hosek of Stroger Hospital of Cook County that found that CAB-LA for HIV PrEP was found to be safe, tolerable, and acceptable to sexually active adolescent females under the age of 18 in three African countries, where young women and girls are disproportionately affected by HIV.

Finally, Dr. Dieffenbach highlighted a real-world demonstration study by Dr. Monica Gandhi of the University of California San Francisco that found that long-acting antiretroviral treatment (LA-ART) given every four to eight weeks and delivered with comprehensive support services suppressed HIV in people who were previously not virologically suppressed and who experienced housing insecurity, mental illnesses, and substance use disorders. Notably, the study participants included individuals who were on ART but were not virally suppressed and others who were not on ART, which would generally make them ineligible to start LA-ART. Dr. Gandhi reported that all of those participants achieved viral suppression on LA-ART, concluding that LA-ART can be effective for individuals facing challenges to adhering to daily oral ART, particularly when combined with wrap-around services to address challenges such as unstable housing, mental health issues, and/or substance use disorders. Read more about this study.

HIV Cure News

Dr. Dieffenbach addressed news that broke while the conference was taking place about another case of an apparent HIV cure. He briefly discussed the 53-year-old man known as “the Dusseldorf patient” who is in long-term HIV remission nine years after a stem-cell transplant and five years after stopping ART. He is one of a handful of people with both HIV and leukemia who received HIV-resistant stem cells through a bone marrow transplant intended to treat leukemia, a very serious and potentially life-threatening procedure. Dr. Dieffenbach explained that this approach is not one that can be used with all people with HIV because of the very high health risks of a stem cell transplant. But this case does provide researchers with insights into possible paths to a more scalable HIV cure.

COVID Treatment and Prevention

Research on COVID-19 is also being discussed at CROI and Dr. Dieffenbach discussed two studies of interest. The first involved research on the investigational drug ensitrelvir, a protease inhibitor, which demonstrated a significant reduction in the time to resolution of five typical COVID symptoms and was well tolerated. In his presentation of the study findings, Dr. Takeki Uehara of Shionogi & Co. also noted that early analysis suggests that the drug may have an impact on long COVID. Dr. Dieffenbach noted that the NIH-support Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG) is conducting a study, called ACTIV-2d, of this once-daily treatment for non-hospitalized adults with early COVID-19 and that the trial is enrolling participants. On the COVID prevention front, Dr. Dieffenbach highlighted a study presented by Dr. Paul Bieniasz of Rockefeller University about his lab’s work to develop monoclonal antibodies against the ACE2 receptor to block COVID entry into human cells. The antibodies are now being evaluated in what Dr. Dieffenbach notes is a promising step since this approach would make it much harder for the SARS-CoV-2 virus to evolve around this form of antibody prevention.

About CROI

CROI is an annual scientific meeting that brings together leading researchers and clinical investigators from around the world to present, discuss, and critique the latest studies that can help accelerate global progress in the response to HIV and AIDS and other infectious diseases, including viral hepatitis, COVID-19, and mpox. More than 3,400 HIV and infectious disease researchers from 72 countries gathered in Seattle and virtually for this forum. Among the studies that are being presented are many that were conducted or supported by NIH, CDC, and other federal agencies. Visit the conference website for more information; abstracts, session webcasts, and e-posters will be published there for public access in 30 days.

During the first full day of research presentations at the 2023 Conference on Retroviruses and Opportunistic Infections (CROI), HIV.gov spoke with Dr. Carl Dieffenbach, Director of the Division of AIDS at NIH’s National Institute of Allergy and Infectious Diseases (NIAID), about some initial highlights, including the opening session that featured a lecture by Dr. Anthony Fauci and several studies about the use of doxycycline for post-exposure prophylaxis (Doxy-PEP) for sexually transmitted infections (STIs). Watch our conversation with Dr. Dieffenbach below:

Dr. Fauci Reflects on the History of HIV
The opening session celebrated the 30th anniversary of this conference, and Dr. Dieffenbach observed that history was a throughline in several of the opening lectures. Dr. Anthony Fauci, who recently stepped down as Director of NIAID, a position he held since 1984, presented a talk titled “CROI: A 30-Year Chronicle of HIV/AIDS Research Progress,” in which he highlighted several “wow” moments from the history of our understanding of and response to HIV and AIDS and recalled how many significant advances were presented at this conference over the years. Dr. Kevin De Cock traced the history of HIV in Africa, and Yvette Raphael of South Africa reflected on the evolution of the response to HIV among women, particularly in sub-Saharan Africa where they are the most affected population, as well as the vital role of activism and community involvement in clinical trials.

Post-Exposure Prophylaxis for STIs
Dr. Dieffenbach also highlighted three new studies that provided additional information about using a preventive dose of the antibiotic doxycycline within 72 hours after condomless sex to prevent bacterial STIs. First, the DoxyVAC study, presented by Dr. Jean-Michel Molina of the University of Paris Cité, assessed two different strategies to reduce the burden of STIs among gay men on HIV PrEP who had a history of an STI in the prior year. The researchers set out to confirm a previous finding on the effectiveness of the Doxy-PEP strategy and assess whether a second (independent) intervention with the meningococcal B vaccine could also have an impact on gonorrhea incidence. The researchers found that Doxy-PEP significantly reduced the incidence of chlamydia and syphilis and had a significant impact on the incidence of gonorrhea and that the meningococcal B vaccine reduced the incidence of gonorrhea by roughly 50% in the participants who received two doses. Dr. Dieffenbach shared that NIAID is also supporting an ongoing large-scale clinical trial at three sites in the southeast United States studying whether the meningococcal B vaccine also can protect participants from infection with the bacteria that causes gonorrhea.

Dr. Anne Luetkemeyer of the University of California, San Francisco, presented additional data from the Doxy-PEP study that had previously demonstrated the effectiveness of the intervention among men and transgender women who have sex with men. The data she presented helped answer the question of whether this use of doxycycline might cause antimicrobial resistance in the bacterial STIs it is intended to prevent. Her analysis found there was no marked increase in doxycycline resistance among three key bacteria, including gonorrhea and Staphylococcus aureus, which can cause diseases.

However, as Dr. Dieffenbach discussed, a study from Kenya presented by Dr. Jenell Stewart of the University of Minnesota indicates that Doxy-PEP may not be effective for women. The study of 449 young cisgender women who were using PrEP found that the use of Doxy-PEP following condomless sex did not reduce incident STIs in this population. She noted that the findings raised questions for further exploration, such as whether the ineffectiveness of Doxy-PEP in this study could be due to differing drug concentrations in vaginal/cervical tissue vs rectal tissue, low adherence, or antimicrobial resistance.

About CROI
CROI is an annual scientific meeting that brings together leading researchers and clinical investigators from around the world to present, discuss, and critique the latest studies that can help accelerate global progress in the response to HIV and AIDS and other infectious diseases, including viral hepatitis, COVID-19, and mpox. More than 3,400 HIV and infectious disease researchers from 72 countries are gathered in Seattle and virtually this year for this forum. Among the studies that are being presented are many that were conducted or supported by NIH, CDC, and other federal agencies. Visit the conference website for more information; abstracts, session webcasts, and e-posters will be published there for public access in 30 days.