For approximately the past year, the ongoing influenza A H5N1 clade 2.3.4.4b outbreak has been marked by increasing infection of mammalian species with the exception of one species of mammals: humans. Human infections have not only been relatively rare, but also much more mild than prior human H5N1 infections, in which mortality can occur in 50% of cases. Perhaps the severity is clade-dependent, but severe disease has occurred in other mammalian species naturally infected — such as cats — with the 2.3.4.4b clade.
Beginning in March 2024, the outbreak took on yet another new characteristic when dairy cattle were added to the list of mammals infected with this virus. Subsequent human infections in the U.S. from these cattle (as well as from poultry) are a current infectious disease crisis. The outbreak in this newly impacted species, and the consequent risk to humans, raises very important questions, the answers to which will be relevant to how the response evolves and is optimized.
Surveillance Gaps
To adeptly manage an emerging infectious disease outbreak, situational awareness is a prerequisite — and is precisely what is missing from this cattle-related outbreak.
Most experts in public health and infectious disease assume that the official tally of affected states and herds is an underestimate, and that the more we test, the more spread will be detected. Currently, the U.S. Department of Agriculture only requires testing when dairy cattle cross state lines, and many state departments of agriculture have no requirement for testing asymptomatic cattle. This state of affairs makes it very difficult to know the full breadth of infection or where the U.S. is on the epidemic curve, leading me to conclude that H5N1 endemicity in dairy cattle is increasingly likely.
Even more important than gaining insight into the cattle infection prevalence is the need to understand the real infection rate among humans. Dairy farm and poultry workers — who comprise the exclusive list of known human H5N1 infections in the U.S. — are also likely undercounted and under-tested. The stigma and resistance to being tested have constrained our ability to understand how frequently the virus spills into humans, what the specific risks are, whether there is any onward human transmission to contacts, and what the spectrum of illness may be.
As of this writing, only around 200 humans have been tested for H5N1 in the U.S. since the cattle outbreak began, and there has been limited, although somewhat reassuring, serologic testing done of contacts of cases and asymptomatic workers (though anecdotal reports have been noted of dairy farm workers with flu-like symptoms or conjunctivitis — the latter the result of the fact that the chief manner in which dairy cattle are passing the infection to humans is when their infected milk contacts workers’ eyes). Serologic testing of unpasteurized milk drinkers should also be pursued.
The more testing that is done, the better we will be able to calculate risk and assess mammalian adaptation of this strain.
Vaccination of Farm Workers
Given the specific and unique threat faced by farm workers, the question of offering stockpiled H5N1 vaccines as protection is an important one to consider. Indeed, Finland has begun the process. However, it is unclear what the threshold for offering the vaccine should be. Certainly, Finland, with zero human or cattle cases reported, is being proactive — but should other nations follow suit?
The stockpiled vaccines are not matched to the current clade of H5N1 infecting cattle and causing the major poultry outbreaks, but they are likely to prevent severe illness. At the same time, severe illness doesn’t seem to be occurring in infected humans, and it’s unclear whether a mismatched vaccine would prevent mild illness (akin to mismatched seasonal influenza vaccines).
So, in the absence of severe human disease, should vaccination be offered against this strain only when matched vaccines are available? It is also important to minimize the risk of dual infections with human influenza strains and avian influenza strains by making sure that seasonal influenza vaccination rates are high in farm workers.
Vaccination of Cows and Poultry
There has also been recent consideration of vaccinating cows. While pursuing development of a bovine influenza vaccine is a worthwhile endeavor, I believe it’s equally as important to recognize the unknowns. Namely, no such vaccine exists currently, it is unclear what the efficacy might be, and it is unknown — given that milk plays a major role in transmission — how to optimally deliver such a vaccine. Vaccination of cows should be one possible strategy to consider as we simultaneously explore other approaches to preventing a larger outbreak.
Vaccination of poultry is a practice done in certain countries, but is illegal in the U.S. because of hypothesized concerns about fostering more asymptomatic cases (although many believe there is also concern over stigma against selling vaccinated chickens in the U.S.). However, there has been some softening of this stance for condors (and the vultures that served as their guinea pigs) in the U.S.
Trial Run
In my opinion, and as I have written before, I do not believe this clade of H5N1 is likely to be the cause of an imminent human pandemic, and it appears to be very constrained at efficiently infecting humans and causing severe disease; I believe other strains of avian or swine influenzas are more likely to bear that honor (e.g., H7N9, A/swine/Shandong/1207/2016).
Regardless, the current dairy cattle outbreak is a critical trial run — a trial run that humans must succeed at to put in place the programs, the protocols, and the coordination necessary for when a less forgiving virus inevitably appears.
Amesh Adalja, MD, is a senior scholar at the Johns Hopkins Center for Health Security, and a practicing infectious disease, critical care, and emergency physician in Pittsburgh.
Disclosures
Adalja is currently a consultant, speaker, and advisory board member for BD.
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