I am often asked whether our seasonal flu vaccines could be used to prevent avian influenza (bird flu) infections, and if not, how long would it take to produce and distribute bird flu vaccines. I’ll try to answer both questions in this blog post.
The U.S. government has stored some H5N1 vaccines made in the early 2000’s in our Strategic National Stockpile. That is good, and even better news is that though those vaccines were designed based on three different clades (think strains) that were circulating in Indonesia and Vietnam at that time, tests have shown that these vaccines produce neutralizing antibodies (these are the antibodies that prevent the virus from infecting and entering our cells) to the clade that is currently circulating in the U.S. dairy cattle. The bad news is that there is not nearly enough vaccine were it to be needed.
The government does not disclose the actual inventory in our Strategic National Stockpile, likely for good reason. So, I can’t tell you exactly how much H5N1 vaccine is in the stockpile, however, the limited public reporting suggests that it is a number in excess of 10 million doses, but less than 50 million doses.
How much vaccine would be needed? Assuming that everyone in the U.S. would be eligible (however, none of the currently approved vaccines are approved for children less than 6 months of age), that would be 326.7 million people. All of the currently approved vaccines require two doses to be fully vaccinated. That would require 653.4 million doses of vaccine, less an estimated deduction of 6.4 million doses for children less than 6 months of age who likely would be ineligible for a new total of 647 million doses needed. Of course, there will be many people unwilling to get vaccinated for a variety of reasons, largely because we can expect a significant vaccine disinformation campaign, but as I frequently say, there are no rabies vaccine antivaxxers since the mortality from rabies is 100 percent in the absence of post-exposure vaccination. I would anticipate that vaccine uptake would be higher for avian influenza than for COVID-19 because the case fatality rate is expected to be markedly higher (30 – 50 percent for avian influenza versus 1 – 3 percent for COVID-19) and unlike COVID-19, there is reason to believe that children would be more severely impacted than older adults.
In the most recent year (2023 – 2024 influenza season) for which data is available, approximately 55 percent of children ages 6 months through 17 years received the annual flu vaccine and approximately 45 percent of adults were vaccinated. One would imagine that interest in the avian influenza vaccine would be even higher if we were facing an imminent pandemic threat, but even if we just go with a conservative guess that 50 percent of Americans ages 6 months and above would want the avian influenza vaccine, that would now result in the number of doses of vaccine needed to be 323.5 million.
If we take the high end of the suspected number of vaccine doses in the current U.S. stockpile (50 million), that still leaves a gap of 273.5 million doses. In May of this year, the U.S. Department of Health & Human Services indicated that it was obtaining an additional 4.8 million doses of vaccine that is more targeted to the current H5N1 clade circulating in the U.S. as opposed to the vaccines in the stockpile that were targeted at earlier clades circulating in Indonesia and Vietnam. Those doses were expected to be delivered this past July, but still need to go through the FDA’s approval process. I don’t know whether these vaccines were included in the estimates of the stockpile reserve or not, but if we assume the most optimistic case, that now only reduces the gap in needed vaccine doses to 268.7 million.
In the egg-based production process of influenza vaccines, the influenza virus that we want to design the vaccine for is injected into fertilized chicken eggs and incubated for several days to allow the viruses to replicate. The fluid containing virus is then obtained from the eggs. For inactivated influenza vaccines (which all of the currently approved H5N1 vaccines are), the vaccine viruses are then inactivated (killed), and the virus antigen is purified. The manufacturing process continues with quality testing and review by the FDA, packaging and distribution. This process can take upwards of 6 months from start to finish.
Since 2012, there is a new way that influenza vaccines can be produced called cell culture-based production in which the CDC supplies the influenza virus for the vaccine (in this case an H5N1 virus) to the vaccine manufacturer, who in turn inoculates mammalian cells with the virus in culture and allows the influenza virus to replicate for a few days. Then, the virus-containing fluid is collected from the cell cultures and the virus antigen is purified. The manufacturing process continues with purification, virus inactivation, and testing. Finally, the FDA tests and approves the vaccines prior to release and shipment. Since the 2021 – 2022 season vaccines, those made by this method are entirely egg-free and thus safe for those with egg allergies. The advantage to this methodology is that it does not require fertilized eggs, which could be a very big deal because in an avian influenza epizootic (epidemic among animals), poultry are generally involved and our only current way to manage those outbreaks is to cull all of the poultry on that farm. Obviously, when these outbreaks are occurring throughout our country, this will result in a decrease in supply of chicken eggs. Also, because it is easier to come by the mammalian cells than fertilized eggs, this process can be completed a bit sooner than the egg-based production of vaccines.
The point of all this is to state that as of right now, we don’t have near enough vaccine to respond quickly to an avian influenza epidemic. Current avian influenza vaccine contracts between suppliers and the government would increase the supply by another 10 million doses, but that vaccine is not scheduled for delivery until the spring of next year. Projections are that in the event of an emergency, 100 million doses could be produced within 5 months. At this rate, it would take nearly a year and a half to produce all the needed vaccine (and recall that I built my estimated need for vaccine based upon roughly half of Americans wanting to get vaccinated).
Our only hope for a faster response would have to include mRNA vaccines, which can be produced much faster than either egg-based or cell culture-based current production methods. Of course, we are also at a time when we are undergoing a transition in presidential administrations. One of the President-elect’s closest advisers on health is a long-time antivaxxer. We also know that there is a movement afoot to try to prevent Americans from having access to mRNA vaccines based on rampant disinformation in large part spread by discredited doctors. If these efforts are successful, and I doubt they will be, we would obviously be seriously hampered in any effort to respond quickly to an emerging bird flu pandemic. The other reason that mRNA vaccine technology may be critical is that avian influenza viruses mutate frequently. Further, as I have previously written, we are entering into the human flu season and this greatly increases the risk for reassortment events, which could significantly alter the effectiveness of current vaccines. Without mRNA technology, a need to change the vaccine formulation to account for antigenic changes in the virus would set back the manufacturing process significantly.
Currently approved H5N1 vaccines:
Arepanrix – Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted. It was approved on November 22, 2013 and is approved for those ages 18 years and older. It is produced using our traditional egg-based technology. The vaccine is given as two injections given 21 days apart. It was made by a subsidiary company of GlaxoSmithKline Biologicals (GSK), but it is not commercially available. Vaccine was produced for purchase by governments for their stockpiles. Last month, the FDA approved its use in children over 6 months of age.
Audenz – adjuvanted influenza A (H5N1) monovalent vaccine. This vaccine was approved in January of 2020. Production of this vaccine utilizes cell-based technologies, rather than egg-based. Audenz is given as a two-shot series 21 days apart. It also is approved for those ages 6 months and older.
Sanofi Pasteur produced an H5N1 vaccine solely for the Strategic National Stockpile and therefore, it has no trade name. It was approved by the FDA in 2007. It is an inactivated, monovalent vaccine for injection and approved only for those ages 18 years and older. It also is given as a two-shot series, but at an interval of 28 days apart. This vaccine is produced by egg-based technologies.
Now, I turn to the question as to whether our seasonal (annual) influenza vaccines might effective in protecting us from avian influenza. Until recently, I would have said not likely. However, this paper 36492242, was just posted online last week. This is an observational study in which sera from people born between years 1925-1967, 1968-1977, and 1978-1997 [if you are curious as to why these birth cohorts were chosen, it was to determine whether the immune responses of the age cohorts might be affected by the different influenza viruses that may have primed their immune responses. There were influenza pandemics in 1957 (H2N2), 1968 (H3N2) and 2009 (H1N1). The first cohort would have lived during the 1957 pandemic and likely primed by exposures to H1N1 (in circulation from the 1918 pandemic) and H2N2 viruses. The second cohort would have lived during the 1968 pandemic and thus may have been primed by exposure to the H3N2 virus. These different exposure histories might affect any cross-reactivity to the current novel H5N1 virus.] were collected before vaccination with 2021-2022 seasonal flu vaccine, 28 days following vaccination and 6 months post-vaccination with an inactivated seasonal influenza vaccine (i.e., the same seasonal flu shots most of us get). Then, haemagglutination inhibition, viral neutralization, and immunoassays were performed to assess the baseline protective immunity of the population as well as the ability of seasonal influenza vaccines to induce protective responses.
The investigators found that subtype-specific serological protection against H5N1 in the representative Spanish population evaluated was limited or nonexistent. However, seasonal vaccination was able to increase the antibody titers to protective levels (a caution here – we don’t know what level of neutralizing antibodies is required for protection against H5N1 infection, but the investigators made a reasonable assumption that it would be similar to the level required for other influenza A viruses, so the conclusion is likely incorrect if the assumption is incorrect) in a moderate percentage of people, probably due to cross-reactive responses. These findings demonstrate the importance of vaccination and suggest that seasonal influenza vaccines could be used as a first line of defense against an eventual pandemic caused by avian influenza viruses, to be followed immediately by the use of more specific pandemic vaccines (i.e., a specific H5N1 vaccine). This is a very important finding as it suggests that we may be able to buy some time while we are waiting for H5N1-specific vaccine to be produced by vaccinating people with the seasonal flu vaccines. In this study, that protection was lost by six months, so this may be a bridging strategy, but not a long one, or alternatively may require boosting, although that was not tested in this study.
The world’s population as a whole (I qualify this because there are some regions of the world that have experienced H5N1 outbreaks and survivors would be expected to have some degree of protection) does not have prior exposure to H5 nor preexisting H5-specific antibodies. However, there is more antigenic similarity between H1 (that we are regularly exposed to through infection and/or vaccination) and H5 than there is between the two hemagglutinin proteins that cocirculate each flu season in the U.S. (H1 and H3).
The neuraminidase (N) protein is also capable of stimulating an immune response and the production of neutralizing antibodies. While this study did not confirm this, perhaps because neither Spain nor the U.S. were as strongly impacted by the 2009 H1N1 pandemic as other countries, some have postulated that people who were infected with that pandemic virus, and perhaps those who were vaccinated with the 2009 pandemic virus, may have greater cross-reactive protection from antibodies specific to the N1 protein, and this may explain why we generally see more severe disease in younger people compared with older individuals. While neither the U.S. nor Spain were hard hit by the 2009 pandemic (thus, any cross protection that may exist may not exist in the majority of Americans), the U.S. did have more infections than Spain, and therefore, while protective antibodies were not detected among this Spanish population, it is possible that some Americans might have these. The N protein antigen is minimal in the inactivated vaccines, and thus N1-specific antibodies may not be significantly recalled after vaccination, however, it is possible that the live, attenuated nasal vaccines, which have been shown to induce stronger cell-mediated responses to N proteins, could be an option and this is worth studying to determine whether an increase in protection might be obtained from these vaccines in the short-term to help protect the population until more specific vaccines can be produced and distributed.
In the meantime, we need to continue research in this area. One exciting possibility is a “pan” influenza vaccine in early clinical trials that could include all the known hemagglutinin antigens of avian and human influenza viruses that might give us even better protection until a specific targeted vaccine could be produced and distributed.
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