An experimental vaccine designed against the highly pathogenic avian influenza H5N1 (HPAI H5N1) virus circulating in U.S. cattle was fully protective in research mice in a new study published in Nature Communications. NIAID scientists at Rocky Mountain Laboratories (RML) in Hamilton, Montana, led the animal study with colleagues from HDT Bio in Seattle who developed the replicating RNA vaccine (repRNA) platform.

Along with confirming that a single immunization with the experimental vaccine was effective against the new flu type in cattle (HPAI A H5N1 clade 2.3.4.4b), the study also allowed scientists to evaluate the vaccine method for “cross protection.” Would it work against the new virus if designed with components used in stockpiled vaccines from an older H5N1 virus (A/Vietnam/1203/2004)? They found that when the test vaccine used a design from the older H5N1 virus, protection was diminished. The findings suggest that the HPAI H5N1 circulating in the U.S. may be able to evade immunity from older H5N1 viruses.

Scientists designed the repRNA vaccine to express the protective vaccine components, as well as the RNA replication machinery derived from an alphavirus. This allows for robust expression of the protective vaccine components upon delivery with LION™, a proprietary nanoparticle formulation. The repRNA/LION technology is the basis of a vaccine that received emergency use authorization in India for COVID-19. Additional applications of repRNA/LION are advancing toward clinical trials for other serious viral diseases after showing effectiveness against several different viruses in the lab.

Scientists at RML and HDT Bio are continuing to develop the vaccine platform, and evaluations in animal models developed at RML are ongoing.

Reference: D Hawman, et al. Clade 2.3.4.4b but not historical clade 1 HA replicating RNA vaccine protects against bovine H5N1 challenge in mice. Nature Communications DOI: https://doi.org/10.1038/s41467-024-55546-7 (2025).
 

Although antiretroviral therapy (ART) is safe and highly effective at treating HIV, some HIV variants do not respond to most ART regimens. Those HIV variants are known as multidrug-resistant (MDR) HIV. People who acquire or develop MDR HIV have few treatment options and a greater likelihood of experiencing or dying from HIV-related complications. A study from NIAID researchers published in Nature Medicine found that a novel treatment regimen including an investigational monoclonal antibody (mAb) called UB-421 (semzuvolimab), and the Food and Drug Administration (FDA)-approved antiretroviral drugs (ARVs) including lenacapavir, suppressed HIV in a person with MDR HIV. This finding could pave the way for further research and development on a novel treatment approach for people with MDR HIV.

MDR HIV can occur in people who have been prescribed an ART regimen that does not fully suppress HIV replication, had a lapse in treatment, or acquired MDR HIV directly. While MDR HIV is relatively uncommon in high-resource settings, it is an increasing threat to people with limited access to quality health care. In the new study, the researchers aimed to identify a regimen that could be used to manage MDR HIV in people with limited treatment options. UB-421 was included in the regimen because prior studies have shown that it may be effective against drug-resistant HIV variants. The regimen also included lenacapavir, which is currently used for the treatment of MDR HIV, and the ARVs tenofovir and emtricitabine. Because drug-resistant HIV variants continue to emerge, the researchers are investigating new avenues of treatment for people with MDR HIV.

The study was led by Tae-Wook Chun, Ph.D., chief of the HIV Immunology Section in NIAID’s Laboratory of Immunoregulation, and conducted at the Institute’s HIV Outpatient Clinic. The regimen was evaluated in a man with MDR HIV and Kaposi sarcoma (KS), a rare cancer that occurs in people with suppressed immune systems. The 58-year-old participant had taken several ART regimens over three decades living with HIV and developed resistance to all available antiretroviral drugs. Analysis of virus from the participant indicated that it was also resistant to nearly all currently licensed and investigational mAbs except for UB-421. During the 70-week treatment period, the participant received UB-421 and lenacapavir-based ART to suppress HIV replication, as well as the antibiotics trimethoprim/sulfamethoxazole and azithromycin, and chemotherapy and immunotherapy drugs for KS.

Within two weeks of beginning the regimen, the levels of HIV in the participant’s blood rapidly decreased. HIV levels continued to decrease at a lower rate for the next 30 weeks. The researchers also found that the participant experienced an increase in the levels of immune cells called CD4⁺ T cells, indicating a recovery in the patient’s immune system. UB-421 acts by attaching to the surface of the T cells at the CD4⁺ T-cell receptor, preventing HIV from binding and thus blocking a critical step in HIV infection. Examination of the participant’s T cells found that UB-421 fully blocked the CD4 receptors during the majority of the treatment period. The regimen suppressed replication of MDR HIV in the patient, lowering the level of virus in the blood serum below the detection limit of 20 particles per milliliter after one year of treatment.

This study lays the groundwork for possible new treatments for people with MDR HIV for whom treatment options are limited. The authors note that UB-421 is a promising therapeutic alongside ART regimens for MDR HIV. These findings also support the evaluation of the study treatment regimen in a larger group of people. 

Reference:

• M Ali Rai. Treatment of multidrug-1 resistant HIV using a novel anti-domain 1 CD4 antibody and an injectable long-acting antiretroviral drug. Nature Medicine DOI: 10.1038/s41591-024-03357-0 (2025).

Subclinical Disease in Monkeys Exposed to H5N1 by Mouth and Stomach

A new study published in Nature found that highly pathogenic H5N1 avian influenza virus (HPAI H5N1) administered directly into the mouth and stomach of research monkeys caused self-limiting infection with no recognizable clinical signs of disease. By comparison, other routes of transmission resulted in mild or severe disease. The findings suggest that drinking raw milk contaminated with H5N1 virus can result in infection but may be less likely to lead to severe illness. Nevertheless, exposure by raw milk – which is a source of several foodborne illnesses – should be avoided to prevent H5N1 infection and potential further spread.

The research team, from NIH’s National Institute of Allergy and Infectious Diseases (NIAID), exposed cynomolgus macaques to the same clade 2.3.4.4b HPAI H5N1 virus circulating in U.S. cattle. Transmission routes included via the nose, windpipe (trachea) or directly into the mouth and stomach to mimic infection routes in people. Animals exposed via the nose and windpipe became infected, developed pneumonia and had varying degrees of disease. Animals infected in a manner that mimicked drinking had a more limited infection with no obvious disease signs. To what extent this work mirrors human infection remains unclear.

The study does suggest that infection through contaminated liquids like raw milk represents a risk for HPAI H5N1 infection of primates. The work cites the “local environment” in the stomach as potentially inactivating the virus and thus, possibly reducing the exposure dose. Scientists at NIAID’s Rocky Mountain Laboratories in Hamilton, Montana, led the work.

They exposed six animals each via the nose to mimic an upper-respiratory tract infection; the windpipe to mimic a lower-respiratory tract infection; and in the mouth and stomach to mimic consuming contaminated products. They used a dose of virus close to what has been found in contaminated raw milk. Researchers regularly monitored and examined animals for up to 14 days.

Animals exposed in the mouth and stomach became infected but showed no signs of influenza illness throughout the study. Animals exposed in the nose showed mild respiratory disease, peaking at day 10. Animals exposed in the windpipe showed severe respiratory illness within a week.

Reference: K Rosenke, A Griffin, F Kaiser, et al. Pathogenesis of bovine H5N1 clade 2.3.4.4b infection in Macaques. Nature DOI: 10.1038/s41586-025-08609-8 (2025).