Although the bird flu has been out of the news lately, it has not gone away, and researchers continue to develop a vaccine for the disease. The good news is that there are some promising early results for one intranasal (no needles) vaccine.

This article will review bird flu and the new results of the phase 1 trial for an intranasal vaccine for bird flu.

What is the bird flu?

Avian influenza, also known as “bird flu,” is a type A influenza subtype designated as A(H5N1). The designation is based on antigens common to this influenza subtype.

Avian influenza viruses are classified into subtypes, which are named according to subtle variations in the structure of two key proteins on the virus surface — hemagglutinin (H) and neuraminidase (N). The virus attaches to the hemagglutinin protein, allowing it to infect the cells.

In general, H1 and H3 flu subtypes are best able to attach to human cells, while H5 is best at attaching to bird cells. However, H5 could mutate to become more effective at attaching to human cells, which would lead to human-to-human transmission of the disease.

Another avian influenza is designated as A(H5N9), but the current bird flu outbreak appears to be the H5N1 subtype. Thus, H5N9 and H5N1 have the same hemagglutinin protein, but different neuraminidase proteins.

As the name implies, these viruses usually affect birds but can occasionally pass from birds to humans, cattle, pigs, and other animals. The H5N1 subtype arose in Asia a few years ago and has spread worldwide. It is highly pathogenic (meaning it can cause disease in humans) and has been passed to humans several times.

Infected birds shed the virus through their saliva, mucous, and feces. Human infections with bird flu viruses occur when the virus gets into a person’s eyes, nose, or mouth, or is inhaled. This can happen when the virus is in the air (in droplets or possibly dust) and a person breathes it in, or when a person touches something that has the virus on it and then touches their mouth, eyes, or nose. Human infections with bird flu viruses have occurred most often after unprotected contact with infected birds or surfaces contaminated with bird flu viruses. However, some infections have been identified where direct contact with infected birds or their environment was unknown.

There are numerous cases where bird flu has been transmitted between humans, but most human infections arise from constant contact with infected birds. Human infection with avian influenza A virus poses pandemic potential, so CDC and other public health agencies investigate every case to assess whether human-to-human transmission might have occurred. Detailed public health investigations can help determine whether person-to-person spread of an avian influenza A virus occurred.

The signs and symptoms of bird flu infections in humans can range from nothing to severe. The infections are similar to other flu infections, including fever, cough, sore throat, runny or stuffy nose, muscle or body aches, headaches, fatigue, and shortness of breath.

We don’t know much about the mortality rate from the bird flu. However, since humans lack immunity to the flu, a large outbreak or, worse, a pandemic, could lead to a much higher rate of hospitalization and death than the current circulating flu subtypes.

Bird flu intranasal vaccine study

In a paper published on 6 November 2025 in Nature Communications, Justin R. Ortiz, MD, Center for Vaccine Development and Global Health, University of Maryland, Baltimore, and coauthors, studied the immune responses among the three groups that received one of three doses of the adjuvanted clade 2.1 influenza A/H5 recombinant hemagglutinin glycoprotein (rH5) vaccine (Novavax).

The reason an intranasal vaccine was initially developed is that intramuscular flu vaccines trigger systemic immune responses that can prevent symptomatic illness, but they can be less effective at preventing transmission and infection. Intranasal vaccines, such as the one in this study, stimulate an immune response at the entry points where flu viruses infect the body. This may provide better protection against transmission and viral shedding. But assessing their systemic immune impact can be challenging.

For this phase 1 clinical trial, the researchers randomized 40 healthy volunteers, aged 18-45 years, to one of five groups, each with eight individuals. Three groups received the rH5 vaccine at 25, 50, or 100 mcg, with a nanoemulsion adjuvant. One group received an unadjuvanted vaccine at 100 mcg, and the last group received a placebo. All groups received two doses, at day 1 and day 29. The trial ran from July 2022 to October 2023.

All five groups had a low baseline immunity to H5N1.

Here are the key results:

• At day 225, four weeks after the vaccine dose, the geometric mean fold rise (GMFR), a statistical measure used to assess the increase in values such as antibody titers in vaccine studies, to the rH5 clade 2.1 was 17.4 in the low-dose adjuvanted group, 3.7 for the medium-dose group, and 14.7 for the high-dose group. The GMFR in the unadjuvanted group was 1.1, and 1.6 in the placebo group. This means that the lowest dose adjuvanted bird flu vaccine had the highest antibody titers.
• Against the rH5 clade 1, the GMFR at day 225 was 20.7 in the low-dose adjuvanted group, 3.1 in the medium-dose group, and 10.4 in the high-dose group. The GMFR in the unadjuvanted group was 7.2 and 2.2 in the placebo group.

Summary

Although the results are exciting, I need to make two key points:

• First, this study did not show effectiveness against wild bird flu subtypes. This study showed a strong immune response to the adjuvanted vaccine, especially at the lowest dose.
• Second, this is a very small study, which is typical of phase 1 clinical trials. We can be more comfortable with the safety and effectiveness of this vaccine from phase 2 and 3 clinical trials.

Nevertheless, it’s important to get ahead of any potential bird flu outbreaks with a new vaccine. The fact that this is an intranasal vaccine might lead to higher uptake.

As I usually say, with phase 1 clinical trials, we need to wait until larger studies are completed and published. But this is very good news.

Citations

• Deming ME, Toapanta FR, Pasetti M, Golding H, Khurana S, Hamouda T, Fattom A, Liang Y, Tennant SM, McGilvray MF, Bernal PJ, Oshinsky JJ, Datta S, Booth JP, Coughlan L, Neuzil KM, Costley CD, Kotloff KL, Sztein MB, Ortiz JR; rH5 Writing Group. An intranasal adjuvanted, recombinant influenza A/H5 vaccine primes against diverse H5N1 clades: a phase I trial. Nat Commun. 2025 Nov 6;16(1):9321. doi: 10.1038/s41467-025-64686-3. PMID: 41198655; PMCID: PMC12592354.

Help the Skeptical Raptor keep writing about new vaccines

There are four ways you can help contribute to keeping this website running at full speed:

1. GoFundMe.
2. Subscribing via Patreon.
3. Buying on Amazon.
4. Sharing this article on Social Media.