Though it can lead to confusion, I can’t think of a situation where having more options as to vaccines wasn’t a good thing.

For the COVID-19 vaccines, having the Novavax option was a good solution for those who have fears stoked by prominent antivaxxers who have spread all kinds of disinformation about the mRNA vaccines altering our DNA (this would flunk them out of the first year of medical school) or a completely made-up assertion, unfortunately perpetuated by a state public health official and amplified by this same group of disinformation purveyors, that the Pfizer vaccine contains DNA coding for the Simian Virus 40 protein (it doesn’t, and even if it did, the vaccine production process would destroy the DNA to the point that the protein wouldn’t be capable of coding for the production of the protein) and that this will now lead to the vaccine causing cancer (it hasn’t and won’t). But, it is understandable that some of the lay public has heard such disinformation and is hesitant to get the vaccines as a result. Therefore, Novavax, which is based on protein technology that has been used safely in the U.S. and around the world for decades, may be a good choice for these folks to put their minds to rest since no genetic material (RNA or DNA) is used in the process of making the vaccine, nor is any contained in the vaccine.

Novavax is also a welcome addition to our COVID-19 vaccine offerings for those who have had significant reactogenicity (side effects like sore arm, swelling or redness at the injection site, fever, headache, muscle aches, etc.) since Novavax has repeatedly been shown to have far less reactogenicity.

On the flu vaccine front, the FDA gave us great news two days ago when it approved a nasal spray influenza vaccine that has been and continues to be available through health care providers, but now can be purchased at the pharmacy with a prescription and taken home for self-administration. This is the first flu vaccine that has been approved for self-administration, which may improve the convenience and access to the vaccine. Also, there are not an insignificant number of people (and especially children) who are afraid of needles, so this vaccine may encourage them to get the influenza vaccine that they might otherwise not get.

This influenza vaccine is called FluMist. It was first approved in 2003 (in 2003, the lower end of the age limit was 5 years, but in 2007, the FDA lowered that to 2 years of age) and covers human seasonal influenza A and B viruses (not the avian influenza or bird flu that you may have seen in the news lately), and is approved for persons aged 2 – 49 (that may seem strange to you; more on that below).

One difference between the nasal vaccine and the “flu shots” is that the nasal vaccine contains an attenuated (weakened) form of live influenza virus. Because the virus is not “killed” or “inactivated,” it does produce a more vigorous immune response in the nasal passages, and as a result can cause low-grade fever in children (particularly under age 6) and in all recipients, the most common side effects are runny nose and nasal congestion. Adults who report side effects are more likely to report a sore throat.

We are told that for those who wish to self-administer the nasal vaccine (age 18 and over) or who wish to administer the vaccine to a person under the age of 18 in their household, you will go to the website of a third-party online pharmacy and fill out a screening and eligibility assessment. If eligibility is confirmed, the pharmacy will write the prescription and ship the vaccine to the address provided.

Who should not receive the nasal spray influenza vaccine?

• Children under the age of 2 years;
• Adults 50 years old and older;
• Anyone with a history of severe allergic reactions to an ingredient of the vaccine or to a previous dose of any of the influenza vaccines;
• Children ages 2 years – 17 years of age who are on aspirin or salicylate-containing medications (these children are at increased risk for Reye’s Syndrome with live virus);
• Children ages 2 years – 4 years with a history of asthma or wheezing in the prior year.
• Anyone who is immunocompromised (they should receive the flu shots with inactivated virus);
• Anyone who resides with severely immunocompromised persons unless they can isolate themselves for a week following administration of the vaccine;
• People who’s spleen has been removed (usually following trauma like a car accident) or who have a non-functioning spleen (for example, sickle cell disease);
• Anyone who is pregnant (this is precautionary; the vaccine does not appear to be absorbed systemically and there has been no documented transmission or adverse effects to the fetus, but it is considered prudent to administer the inactivated influenza vaccine to pregnant women);
• Anyone with a CSF (cerebral spinal fluid) leak connecting to their mouth, nose, ear, or other place within the skull (for example, as a result of surgery or trauma);
• Persons with cochlear implants;
• Anyone who has recently taken influenza antivirals (oseltamivir or zanamivir within 48 hours; peramivir within 5 days; or baloxavir within 17 days). This is because influenza antivirals can reduce the effectiveness of a live virus vaccine.

Further, if you are older than 5 years old with asthma; have underlying medical conditions; have an acute illness, especially another infection; or have a history of Guillain-Barre Syndrome, talk to your doctor before ordering the FluMist vaccine. There was an elevated risk for Guillain-Barre Syndrome with the 1976 swine flu vaccine, but no association has been noted with vaccines subsequent to 1976 (we have not used swine flu viruses for vaccines since 1976). Thus, the risk for this condition appears minimal, but we nevertheless would generally not administer this vaccine to anyone who has been experiencing or recovering from Guillain-Barre Syndrome within the prior 6 weeks.

The age cut-off of 49 years for FluMist will seem strange to some readers, as this is unusual. As far as I can tell, it is based upon one study that did not show effectiveness of the vaccine in those in the age group of 50 – 64 years. There are certainly methodological criticisms that can be made about this particular study, but nevertheless, absent another study demonstrating effectiveness in this age group, the age restriction is appropriate. Further, those who are ages 65 years and older should receive the high dose or recombinant influenza vaccines (FluMist only comes in one dosage formulation). Suitable vaccines for those 65 years and older include:

• High-dose inactivated influenza vaccine (HD-IIV3, Fluzone High-Dose)
• Recombinant influenza vaccine (RIV3, Flublok) or
• Adjuvanted inactivated influenza vaccine (allV3, Fluad).

Finally, keep in mind that the immunity from all influenza vaccines wanes and therefore, even though it is currently being offered and promoted by some pharmacies, it is best to wait until we start seeing rising cases of influenza where you live before getting the vaccine so that it will give you the greatest protection for the entire flu season, which can certainly last as long as 6 months. If you follow me on X or on the Idaho Matters radio show, I will let you know when I think the ideal time is to get your vaccines as we watch the influenza activity here in Idaho and around the country.

We saw an unprecedented global outbreak of the monkeypox virus clade IIb in 2022 that was eventually contained to some degree with education and vaccination of those at highest risk for infection, which for the most part appeared to be men who have sex with multiple male partners.

Most recently, a new outbreak of monkeypox virus clade Ib is happening in African countries that have never had clade I infections, which appear to be transmitted both by close contact and through heterosexual sexual contact. Clade Ia has been known to have a case fatality rate of three to ten times that of Clade IIa infections, but there is little doubt that the lack of health care access and infrastructure in Africa contributes to a higher mortality rate than would be expected in more developed countries. Further, both Clade Ia and Ib infections appear to be far more frequently occurring in children who can suffer higher mortality rates.

The outbreak was declared a public health emergency for the African continent by the African CDC, and then shortly thereafter, was declared a Public Health Emergency of International Concern (PHEIC) by WHO. Almost immediately thereafter, a small number of cases of Clade Ib cases were detected in other countries where citizens had traveled to Africa.

At long last, vaccines are beginning to be delivered to Africa, however, the amounts are far less than that required to vaccinate a sufficient part of the population to ensure that we can bring the outbreak under control and prevent more cases from appearing in countries throughout the world.

One strategy used in combating the Clade IIb outbreak was to administer the vaccine intradermally (immediately under the skin) at 20 percent of the usual dose given subcutaneously (a short needle that goes beyond the skin but stops short of the muscle). This method would then allow a single dose of vaccine delivered in the typical subcutaneous fashion to be stretched out to five doses by using the intradermal route. If this strategy generates the same or better immune response, it would allow us to vaccinate many more of those in Africa giving us a better chance of containing the spread of Mpox, especially since the normal vaccination schedule calls for a second dose to be administered one month later.

A paper entitled: “Reactogenicity and immunogenicity against MPXV of the intradermal administration of Modified Vaccinia Ankara compared to the standard subcutaneous route” was published as a preprint just several days ago Reactogenicity and immunogenicity against MPXV of the intradermal administration of Modified Vaccinia Ankara compared to the standard subcutaneous route | medRxiv, and offers us important insights. This study compared the reactogenicity (local and systemic reactions from the vaccine administration) and immunogenicity (strength of the immune response generated by the vaccine) between these two doses and routes of administration when this vaccine strategy was used in 2022 in Rome.

It was discovered that the intradermal route actually generated slightly higher levels of IgG specific (to monkeypox) antibodies, as well as slightly higher neutralizing antibodies (recall that neutralizing antibodies are those that bind to the virus and interfere with the virus’ ability to infect and enter a cell. You may recall from my prior blog posts that the antibody response is part of our humoral immune response. It certainly appeared that the lower dose given intradermally stimulated an equally, or slightly better, humoral immune response.

However, we had little data as to the effect of these different doses and routes of administration on the cellular immune response. Antibodies cannot enter cells, so their effectiveness is primarily directed at preventing virus from infecting cells. However, once cells are infected, it is the cellular immune response that is primarily directed at killing infected cells, and thereby killing the virus that has infected the cells, and at clearing the virus from the body to eliminate persistence of infection.

The wonderful news from this study was that the cellular immune response was equally stimulated by either route of administration, even considering the reduced dose with the intradermal route.

Finally, not surprisingly, the intradermal route was more reactogenic, however, both routes of vaccine administration were well tolerated by vaccine recipients.

With these findings, I hope that the African CDC, WHO and other groups who are assisting with the vaccine roll-out in Africa will authorize and utilize the intradermal, dose-sparing method so that we can vaccinate a much larger number of people quickly, though of course this study was conducted on Clade IIb virus and we cannot be sure the same results would be attained with Clade Ib, but there is reason to be optimistic, even while those studies are done to confirm. The downside is that intradermal administration is technically more difficult, but generally, most people can be taught the proper technique and don’t require too much experience to become proficient at it.

How is Transmissibility to Humans Evolving and How are we doing Managing the Pandemic Risk?

To answer these questions, I am going to review two recent articles with you: “Pathogenicity and Transmissibility of Bovine H5N1 Influenza Virus” Pathogenicity and transmissibility of bovine H5N1 influenza virus | Nature published in Nature in July of this year and “How Policy Makers Can Act Now To Prevent An Avian Influenza Pandemic” How Policy Makers Can Act Now To Prevent An Avian Influenza Pandemic | Health Affairs published in Health Affairs this month.

As I have written about previously, H5N1 is an avian influenza virus (“bird flu” as it is colloquially referred to) that normally infects waterfowl, who in turn infect domestic poultry and sometimes wild birds through contamination of their food and habitats with droppings as these waterfowl fly over or temporarily land in these habitats. The H5N1 influenza virus (a type A influenza virus, but not one of the human seasonal influenza viruses) infects birds by binding to α 2, 3 – sialic acid residues on cell surfaces that are abundant in birds. Fortunately, prior to 2022, this virus transmitted inefficiently to other mammals and humans, likely due to the fact that most mammals, and certainly it is the case for humans, do not have α 2, 3 – sialic acid attached to a sugar on the cell surfaces in the upper airways, but rather the sialic acid conformation in human upper airways is of the α 2, 6 type. While there have been infections in humans, until this year, these have generally occurred in persons with extensive contact with sick and diseased birds, such as poultry farm workers or those who worked at the culling facilities during outbreaks on poultry farms. Unfortunately, when avian influenza of the H5N1 type has infected humans, the infection mortality rate (# deaths/# recognized infections) has been exceedingly high varying anywhere from 40 – 80 percent, and seemingly posing the greatest threat to young children.

In March of this year, it was recognized for the first time that H5N1 was causing outbreaks among dairy farms in the U.S. Studies revealed that the virus infected the utters of dairy cows and the milk from these cows had extremely high levels of virus in it. It was latter reported that cows’ utters have both α 2, 3 – sialic acid receptors and α 2, 6 – sialic acid receptors raising concern that the infected utters could serve as “mixing bowls” in which the potential exists for cows infected with H5N1 influenza virus (a new revelation) could be co-infected with seasonal human influenza viruses (a long-recognized potential and growing concern as we approach our influenza season given the continued spread of H5N1 virus among dairy cattle). Influenza viruses are known for their “reassortment” proclivity, in which any one of eight gene segments can be swapped from one virus to another. The resultant virus could then potentially have the virulence (potential to cause severe illness or death) of avian influenza coupled with the increased transmissibility of human influenza viruses, significantly raising the potential for a pandemic, as has happened in the past when avian influenza and human influenza viruses infected swine.

The outbreak of H5N1 among dairy cattle has been concerning not only because natural infection of cattle was unknown prior to this year, but also because it is the first time we are seeing convincing evidence of forward transmission among mammals, increasing the concern that the virus is evolving in a manner that might allow the same to happen in humans, a requisite for the virus to be of pandemic potential.

[A note to readers to help avoid confusion. First, although the H5N1 is an avian influenza virus, now that it is spreading among dairy cattle and there is evidence that transmission between cattle is occurring (as opposed to each cow being infected directly from a bird), the virus obtained from cattle (generally in the milk of the infected cow) is referred to by some as “bovine H5N1 influenza virus.” Secondly, since there are limitations to the studies we can conduct on humans relative to infectious diseases, it is common to identify animal models of infection that tend to have similarities to human infections or modes of transmission to facilitate our study of the infectious agent and/or disease it causes. Ferrets are commonly used as an animal model for influenza virus due to the similarities of our respiratory systems. Mice are commonly used to examine the ability of the infectious agent to transmit to the unborn offspring during pregnancy or to their offspring through lactation.]

Mice can become infected with bovine H5N1 virus through ingestion of the infected cow’s milk, and the virus quickly spreads throughout the mouse organs. When the mouse ingests a high dose of virus in the milk, virus can be detected in the nasal passages, lungs and brain of the mouse by day 6. The study showed that mice can also be infected by intranasal inoculation of virus.

The study also revealed that ferrets could be infected by intranasal inoculation of virus and that ferrets can become ill. Virus in the ill ferrets could be detected in respiratory and non-respiratory tissues, including the eyes, brain, colon, liver, spleen, kidney and/or heart.

The investigators showed that infected mice could transmit the bovine H5N1 influenza virus to their pups likely through the milk of the mother. However, it did not appear that the mice could transmit the virus to other adult mice (through respiratory droplets or aerosols).

The investigators tested the potential for infected ferrets to transmit the bovine H5N1 virus by respiratory droplets by infecting some with this influenza virus and others with an H1N1 virus, for which respiratory droplet transmission among ferrets has already been demonstrated, by placing uninfected ferrets in cages in proximity to cages with infected ferrets. The ferrets were tested with nasal swabs every other day. The infected ferrets developed positive tests with high viral titers (suggesting that they should be infectious to the uninfected ferrets if respiratory droplets are a mode of transmission). None of the ferrets exposed to ferrets infected with the bovine H5N1 showed any signs of infection, nor developed positive nasal swab tests. However, one of four exposed ferrets did have low-level antibodies to the H5 virus, which suggests that there is only inefficient transmission of the virus by respiratory droplets in ferrets.

Of concern, the investigators showed that, at least in the laboratory, the bovine H5N1 virus showed the ability to bind both α 2, 3 – sialic acid and α 2, 6 -sialic acids, raising the potential that the virus has already adapted in cows’ utters to be able to infect the upper airways of humans.

The authors of the Health Affairs article argue that this latter finding is concerning, but does not necessarily mean that this virus will spark a pandemic. However, they caution that this situation demands a more vigorous public health response to ensure that it doesn’t. The authors point out that the true assessment of the extent of the H5N1 outbreaks among poultry and dairy farms is severely hampered by the voluntary nature of testing of these farms and the relatively low level of engagement by farmers. Even more lacking is testing of farm workers, which is essential to identifying the extent of spillover transmission to humans and for serial genetic sequencing to detect whether the virus has picked up genetic mutations known to enhance mammalian spread.

I quote the following paragraph from the article that precisely mirrors my thoughts on our response thus far:

Any effective pre-pandemic strategy must be based on sound and timely data. Waiting for H5N1 to declare its presence among humans would be to waste precious time and risk converting preventative measures into futile exercises in rescue and recovery. The COVID-19 pandemic taught the danger of getting caught flat-footed, yet policy makers do not seem to have learned the lesson. 

The authors make another suggestion with which I whole-heartedly agree and was a lesson that should have been learned from the COVID-19 pandemic. That is to set up multiple testing centers across the U.S. to screen for H5 influenza cases and to allow for more prompt sequencing and reporting of positive specimens. They also point out the need for rapid tests for providers, and ideally even for home use, especially by those workers and their families that are currently identified at highest risk of infection.

Adding my own personal thoughts is that this will be increasingly important as we enter into our seasonal flu season in which positive cases of influenza A will likely be assumed to be the seasonal human virus, missing potential cases of H5 infection.

The authors point out the need for rapid initiation of antiviral therapy, the need to avoid delayed antiviral treatment to reduce the risk of antiviral-resistance, and the need for more research and development into more effective antivirals that are effective against all strains of influenza.

The authors point out the very real limitation of our monitoring for infections and investigations of outbreaks among dairy farms in that farmers are reluctant to have virus detected due to the financial harm that could follow and farm workers are reluctant to seek medical attention for illness due to financial limitations, lack of health insurance, and fear of loss of their jobs if they are sick. An adequate public health response will have to address these concerns.

Finally, the authors rightly point out that our current influenza vaccine technology is too slow to allow for a prompt pandemic threat response. Further, given that the avian influenza H5N1 virus is highly pathogenic in poultry and results in a high mortality rate and the need to cull large numbers of poultry to contain outbreaks, it may not make as much sense to rely on an egg-based vaccine method. We must develop new vaccine strategies.

There have been many articles published about neurological sequelae following SARS-CoV-2 infection. In this blog post, we will review two recent papers (“Neurological Complications caused by SARS-CoV-2”, Neurological complications caused by SARS-CoV-2 (asm.org), appearing in Clinical Microbiology Reviews and “Cognitive and Psychiatric Symptom Trajectories 2 – 3 years after Hospital Admission for COVID-19: A Longitudinal, Prospective Cohort Study in the UK”, Cognitive and psychiatric symptom trajectories 2–3 years after hospital admission for COVID-19: a longitudinal, prospective cohort study in the UK – The Lancet Psychiatry, appearing in The Lancet Psychiatry) that summarize much of what we have learned thus far (I have no doubt that we will learn much more in the next ten years) about the neurological sequelae that some people suffer following SARS-CoV-2 infection.

It is notable that as many as 30 percent of patients with COVID-19 present with neurological symptoms. For some time now, we have had evidence that the SARS-CoV-2 virus can infect the brain based upon the findings at autopsy in patients who died from COVID-19 that the viral genetic material could be found within cells of the brain and within the cerebral spinal fluid. It has been clear for some time now that we can see acute infection present with neurological impairments, or neurologic complications can occur weeks to months following seeming recovery from the infection, as well as part of the constellation of symptoms and conditions that occur in association with Long COVID.

There have been a number of mechanisms for SARS-CoV-2 infection of the brain proposed, including the virus entering the neurons of the olfactory nerve at the back of the nose and travelling up the nerve (retrograde neuronal spread) to the brain, spread to the brain during the brief period of time that the virus gets into the bloodstream (hematogenous spread), disruption of the blood brain barrier that normally makes it harder for infectious agents to get access to the brain by multiple mechanisms, including through cytokine storm that has been associated with severe cases of COVID-19 in children and adults, and neuronal fusion by which SARS-CoV-2 infection of one neuron may cause the neuron to abnormally fuse to another neuron allowing the virus to freely move between the fused neurons. SARS-CoV-2 has also been capable of causing neurological complications and conditions other than by direct infection of the brain cells by causing blockages in blood vessels that supply blood to or drain blood from the brain or by the formation of blood clots that travel in the blood stream to the brain, causing a lack of oxygenation (hypoxia) to a portion of the brain resulting in tissue injury or death of brain tissue and neurological deficits related to the particular brain function conducted by the affected part of the brain.

Depending upon the parts of the brain affected and the extent of the involvement, patients with COVID-19 may experience headache, loss of smell or altered smell, loss of taste or altered taste, a range of visual disturbances, sudden weakness or loss of movement of an extremity, confusion, altered mental status (level of cognition or alertness or both), seizures, abnormal movements, dizziness, imbalance, slurred speech or inability to speak, altered gait, tremors, slow movements, increased muscle tone, and impaired memory, persistent ringing in the ears, loss of hearing, among other neurological signs and symptoms.

These signs and symptoms can be manifestations of meningitis, encephalitis, encephalopathy, ischemic or hemorrhagic stroke, and Parkinson’s Disease among others. Further, it has been well established that those at risk of dementia or with early stages of dementia experience an acceleration and worsening of dementia following COVID-19. There has been mounting evidence that SAR-CoV-2 infection of the brain can result in dementia and pathological findings that very closely resemble Alzheimer’s Disease.

There is mounting evidence that those who develop loss of smell with their SARS-CoV-2 infection may be at increased risk of developing neurologic sequelae and neurodegenerative conditions following their COVID-19 illness. We don’t know how long following infection persons may remain at risk for neurological conditions; however, we are gaining mounting evidence that prior infection with certain viruses may cause neurological problems many years later in life, e.g., enterovirus and human herpes virus with amyotrophic lateral sclerosis (ALS), influenza virus with Parkinson’s disease, and Epstein-Barr virus with multiple sclerosis (MS). For a more extensive review of this topic, see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838016/.

“Brain fog” remains one of the most frequent neurological complaints of Long COVID patients encompassing such things as diminished ability to concentrate and focus, confusion, short-term memory loss and/or decreased mental acuity, and cognitive impairments can often be detected on testing.

Patients with preexisting neurological conditions may be particularly at risk for neurological deterioration with SARS-CoV-2 infection, particularly those with Parkinson’s disease or those who are at risk for dementia or have early onset dementia.

Those persons who were hospitalized due to severe COVID-19 may be at particular risk for neurological sequelae. A study of such patients demonstrated that slightly more than half reported awareness of cognitive decline, while all patients tested had worse cognitive scores among all domains of cognitive testing following discharge from the hospital when compared to healthy controls adjusted for sociodemographic factors. In addition, roughly three-quarters of patients reported at least mild depression, a little more than half reported anxiety, and more than a fifth of all patients reported severe depression. Of great concern was the fact that depression, anxiety and fatigue were worse in this group of patients at 2 – 3 years following their illness than they were at either 6 months or 12 months in this patient population, including the occurrence of new symptoms among some patients. Just short of 27 percent of these patients reported an occupational change, most commonly attributed to their poor health, and most commonly and specifically based upon cognitive decline.

There are many potential complications and conditions that can follow SARS-CoV-2 infection. Many of these are distressing and life-altering. In this blog post, I discuss some of these complications and conditions that are neurological or psychiatric in nature. I will discuss other complications and conditions in subsequent blog posts. Given that we cannot predict with confidence who will and who will not develop these conditions, the public would be well-advised to consider the potential for these health consequences in addition to simply the risk for severe COVID-19 or death when considering risk mitigation strategies and COVID-19 immunizations.

The FDA has authorized two new COVID-19 vaccines (Pfizer and Moderna) and is expected to authorize a third (Novavax) in the coming weeks. It is anticipated that the Pfizer and Moderna vaccines may start showing up in some pharmacies as soon as this weekend, with much more availability during the course of next week.

What is different about these vaccines?

All three vaccines are monovalent vaccines, which means that they are based on the spike protein of just one variant. All three vaccines are based on different and more recently occurring variants than the variant that served as the basis for the 2023-2024 updated vaccines that were made available last September (XBB.1.5). The Novavax vaccine that is awaiting authorization is based upon JN.1 and the Pfizer and Moderna vaccines are both based on the KP.2 variant.

Are these new vaccines booster shots?

Technically, no. A booster is another dose of the same vaccine previously administered in order to boost the specific immune response generated by that prior dose of vaccine. In this case, because all three vaccines are new formulations based on more recent variants, they are technically priming doses and will result in new immune cells developing in response to the new variant’s spike protein. For those (see below) who are eligible for a second dose of this vaccine due to age or underlying medical conditions, that second dose next year will be a booster.

Having provided the technically correct answer, there are ways that this priming dose does act in some respects as a boosting dose. For example, let’s assume that you were infected early this year. That infection was very likely due to JN.1 as it was so fit that it basically outcompeted all the other circulating variants and became dominant. If you survived the infection and have a healthy immune system, then you developed an immune response to the JN.1 spike protein. If you were to get the Novavax updated vaccine next month when we expect it to be authorized, then this priming dose will significantly boost the immune response you generated from that prior infection.

The other way in which these priming vaccines will still act in a conceptual way as a “booster” is that there are many parts of the spike protein that serve as antigens (meaning that our immune systems recognize them as not us and something to form antibodies against), and some of those antigens will still be in the new spike protein formulation, and there are other parts of the spike protein that stimulate another part of our immune system that is particularly important in protecting us from severe disease and in clearing the virus from our system that gets boosted with each dose of vaccine we get.

Who can get the new COVID-19 vaccines?

The FDA has authorized the new 2024-2025 Pfizer and Moderna COVID-19 vaccines for those 6 months old and older. The CDC has recommended that everyone 6 months of age and older receive an updated COVID-19 vaccine.

When should you get the new vaccine?

The answer to this question depends in large part on your specific risks, so check with your doctor, but here are some considerations:

1. If you received a second dose of the 2023-2024 updated COVID-19 vaccine (likely due to your age or underlying medical conditions) within the last two months, the CDC’s guidance is to wait until a full two months after that shot to get the new updated vaccine.
2. If you have had COVID-19 within the past three months, the CDC guidance is to wait for a full three months after infection to get the new vaccine.
3. If you are over age 65 or have underlying medical conditions, and especially if you fit into both categories and/or are immunocompromised, and you have not had COVID or a COVID vaccine in the past year, your immune protection has likely significantly waned, and therefore, you should seriously consider getting the new vaccine ASAP, especially since we are experiencing high levels of community transmission.
4. If you have had or have Long COVID, your risks for returning symptoms or worsening of symptoms appears to be increased with another infection, and therefore, you should discuss with your doctor whether you should get the new vaccine now and a second dose in 4-6 months.
5. If you are pregnant, you are at risk for more severe disease than a woman your age who is not pregnant, and there are risks to your unborn child, so discuss the timing for getting the new vaccine with your obstetrician or whichever health care professional is managing your pregnancy care.
6. If you have upcoming travel plans, especially to a foreign country, and want to minimize the chances of illness and hospitalization away from home, consider timing your new vaccine dose at 10 – 14 days prior to your departure. The same advice would be relevant if you have an upcoming event, e.g., a wedding, where there will be a lot of guests, especially many travelling to the event, due to the increased risk of exposures.
7. If you have had significant reactions to the mRNA vaccines (Pfizer or Moderna) or your doctor has advised you not to take them due to a reaction, or if you merely are concerned about mRNA vaccines, you may wish to wait for the Novavax vaccine to become available, which as stated above, is expected in the upcoming weeks. Novavax is a protein subunit vaccine that has a long history of use in making various vaccines and contains no mRNA. It also is much less likely to cause the same degree of side effects (sore arm, swelling, fever, muscle aches) than the mRNA vaccines.
8. For everyone else, this is a tougher question to answer. Right now, levels of transmission are high throughout most of the U.S., however, it appears that we may have just reached the peak and may be headed down. If you are not at high-risk, have kept up with the recommended vaccines, and are able to employ non-pharmaceutical measures to minimize your exposures (for example, working from home, masking when out in public crowds, avoiding large indoor gatherings, etc.) until the levels of community spread decrease significantly, then you may very well want to wait until the next new variant begins to make a surge here in the U.S. (there is already a new variant that is circulating in Europe, but it doesn’t appear to be spreading significantly here in the U.S. yet) in order to try to line-up your highest immune response to the time of greatest risk of infection, especially because if you are in this group, you are unlikely to qualify for a booster dose in the first half of next year, then waiting for the next surge to begin could be a reasonable option.

Which vaccine should you get?

Unless you fall into category 3, 4, 5, 6, or 7, in which case you should not wait for Novavax and get either one of the mRNA vaccines depending upon the advice of your physician, this is a really difficult question to answer, and in fact, there is no correct answer. We do not have recent studies that test these vaccines in head-to-head comparisons.

There is suggestive, but not conclusive, data to support that mixing up the vaccines (such that if you have always received the Pfizer vaccine, to now get a Moderna vaccine, and vice versa) might result is a somewhat broadened antibody response, though the data is not so clear-cut as to make this a formal recommendation. Frankly, if you have tolerated one vaccine in the past, just go ahead and get that one again. On the other hand, if one of the mRNA vaccines caused significant side effects, try the other, or if you are not at high-risk as I described above, consider waiting for the new Novavax vaccine to come out.

The tricky part of the question is whether the mRNA vaccines (based on KP.2) or the Novavax vaccine (based on JN.1) will be most protective against the variants that will emerge over the course of the next year. That is because we don’t know how this virus will mutate and/or recombine in the near future. There is a case to be made for advocating for either option, and in fact, members of the vaccine committee that made its recommendations to the FDA and vaccine manufactures were not all in agreement on this. The arguments for the mRNA vaccines (KP.2) include the fact that KP.2 is more recent than JN.1 and the fact that this variant developed some new, more immune evasive mutations, and since that contributed to increased fitness, those mutations may be more likely to be reappearing in new future variants. However, the exception to that rule already happened in the subsequent variant that followed KP.2 – KP.3.

The other school of thought relates to the evolutionary biology of viruses, and particularly the SARS-CoV-2). If you think of the evolutionary tree much the way you might think of a family tree with which readers are likely more familiar, that tree has a trunk that begins with the oldest ancestor(s), and then has branches that grow off of it depending on the degree of relatedness. Unlike family trees, the evolutionary tree for viruses is not always linear, and this is especially true of SARS-CoV-2. Thus, while one branch seems to be progressing and growing with serial minor genetic mutations, all of a sudden, we see a new variant that is different enough that it is starting a new branch. Thus, this school of thought argues that using the trunk of the tree (in this case JN.1 from which all of the variants we have experienced since the beginning of this year are descendants) would likely result in a closer match to future variants than basing the vaccine on a variant that is from a branch (e.g., KP.2).

You’ll find vaccine experts that are proponents on both sides of the argument, and the fact is that we just don’t know. Time will tell, but two things do appear clear to us. One is that now into our fifth year of the pandemic, every dose of past vaccines has added protection against severe disease – hospitalization and death – no matter how well or poorly matched to the circulating variant at the time of infection. The other is that getting the vaccine reduces your risk of Long COVID by as much as 50 percent. Recall that every infection you get, increases your risk for Long COVID. So, don’t agonize over this decision. Any vaccine is better than no vaccine, and we have every reason to believe that any of these vaccines will reduce your risks for severe disease and Long COVID.

“Sporadic human infections with highly pathogenic avian influenza (HPAI) A(H5N1) virus, with a wide spectrum of clinical severity and a cumulative case fatality of more than 50%, have been reported in 23 countries over more than 20 years. HPAI A(H5N1) clade 2.3.4.4b viruses have spread widely among wild birds worldwide since 2020–2021, resulting in outbreaks in poultry and other animals. Recently, HPAI A(H5N1) clade 2.3.4.4b viruses were identified in dairy cows, and in unpasteurized milk samples, in multiple U.S. states.” https://www.nejm.org/doi/full/10.1056/NEJMc2405371.

This article in the New England Journal of Medicine now provides us with a clinical case report of the infected Texas dairy farm worker.

In late March, the farm worker developed redness and discomfort in his right eye. The worker denied having any fever, chills, cough, shortness of breath or loss or distortion of vision.

The worker denied any contact with dead or diseased birds or poultry. He did report close contact with cows, including cows that were showing signs of possible infection with avian influenza manifested by lethargy, fever, decreased appetite, dehydration, and/or decreased milk production. He did routinely wear gloves, but no other PPE including masks or eye protection.

On physical examination, the patient did not appear severely ill. His lungs were clear.

His eye examination revealed the following:

We are looking at the patient facing us, so the eye on the left side of this photo is actually his right eye, and the eye to our right is actually his left eye. Looking at his left eye, he has conjunctivitis (inflammation of the conjunctiva, which is the superficial lining of the eye and eye lids). We can see that it is red and injected, meaning that we see the blood vessels much more prominently than in someone with a normal-appearing eye. His right eye demonstrates a subconjunctival hemorrhage, in other words, there is bleeding directly under the conjunctiva. We can tell that there is a hemorrhage (bleeding) because the redness is confluent and obscures the blood vessels, whereas in his left eye, we can see the blood vessels much more clearly.

The examiner swabbed the patient’s nose and right eye to test for influenza virus. The test (which looks for genetic traces of virus) of both samples was positive for influenza A and for the H5 protein, which is indicative of avian influenza. That test also suggested that the amount of virus in the eye sample was very high. The CDC performed additional testing that confirmed that the virus was A(H5N1) and genetically the same as the virus detected to be circulating among dairy cows.

The patient was instructed to isolate at home and was started on an oral antiviral medication (oseltamivir). Over the ensuing days, the patient’s conjunctivitis resolved and no family members developed signs or symptoms of infection.

Additional testing of the virus genetic material revealed that it had not mutated in a way that would change the receptor-binding protein from the avian form (α2,3-linked sialic acid [we do have this form or receptors in our eyes]) to the human form (α2,6-linked sialic acid [this is the receptor type in the human respiratory tract]). On the other hand, the virus retrieved from the infected farm worker had acquired a mutation in the PB2 protein that has been associated with adaptation of the bird virus to mammals, including humans. Fortunately, the virus did not have the mutations that we associate with developing resistance to our usual influenza A virus antiviral agents.

My commentary:

This is good news/bad news. The bad news is that apparently cows can transmit the virus to humans who are in close and prolonged contact with infected cows, though we still don’t know how transmission occurred – respiratory droplets from infected cows? Contact with virus in the milk of infected cows and then touching or rubbing one’s eyes? Aerosolization of virus from the milk when cleaning floors or equipment used in milking the cows?

The good news is that the patient did well and appeared to recover well, the virus did not show worrisome changes that would suggest that the virus can now efficiently transmit to and among humans, and the patient did not appear to infect anyone in his household, though we were not provided with any information as to what precautions were used in the home and how many persons were in the home.

There remain many questions besides those I have already raised. One question is whether the antiviral treatment prevented him from becoming more ill and/or did it shorten his course of illness? I also hope that they will carefully follow this farm worker over time. We know that in other mammals, this virus has seemed to produce significant neurological disease. The eyes can be a route for viruses to access the brain. It would be good to follow this patient to ensure he does not develop any signs of neurological disease in the future.

Part III

The A(H5N1) avian influenza outbreak investigation continues to unfold, and we are rapidly gaining new information. This is the third in a series of current updates on the avian influenza outbreaks on U.S. dairy farms.

1.      A study planned for publication in July was released early by the CDC (kudos for that!) entitled: “Highly Pathogenic Avian Influenza A(H5N1) Clade 2.3.4.4b Virus Infection in Domestic Dairy Cattle and Cats, United States, 2024.” Early Release – Highly Pathogenic Avian Influenza A(H5N1) Clade 2.3.4.4b Virus Infection in Domestic Dairy Cattle and Cats, United States, 2024 – Volume 30, Number 7—July 2024 – Emerging Infectious Diseases journal – CDC.

We have learned a lot and I have previously written about the signs of infection in dairy cattle. However, until now, we had been provided with little information on how the disease manifested in cats, other than mentions of neurological defects and rapid decline with resulting death in six cats that were fed milk from infected cows on the farms with outbreaks. This study provides many more details. We are told that the cats manifested a depressed mental state, stiff body movements, uncoordinated movements, loss of vision, a tendency to repetitively move in circles, and abundant drainage from their eyes and nostrils. On examination, the infected cats had lost their menace reflexes (these are reflex movements of the head and eyes in response to a perceived threat that is often tested by the examiner covering one eye and moving their hand quickly towards the other eye without making contact with the cat), which generally suggests some neurological defect between the eye and the neuropathways to the brain. These cats also had a weak blink response and had lost their pupillary light response (the reaction of the pupils of the eye when a light in directed at it) suggesting a neurological defect between the eye and the brainstem of the cats. These findings together suggest very severe neurological impairment.

We also are learning the specifics of some cow deaths. We had previously been given the impression that all of the cows that were infected suffered only mild illness. However, some recent statements seemed to imply that there must have been one or more deaths of cows due to infection. This study indicates that they reviewed tissues from necropsies performed on three cows that were euthanized (suggesting that they must have had more severe disease) and on three cows that died of natural causes, which I take to mean cows that survived and recovered from the infection, but then died for reasons attributed to their advanced age.

The tissue examination of the cows showed mastitis (inflammation of their mammary glands) in the majority of cases and hepatitis (liver inflammation) in three of the cows.

The tissue examination from the cats showed much more severe disease with severe inflammation in the central nervous system and inflammation of their lungs (interstitial pneumonia), heart (myocarditis) and eyes (chorioretinitis). Further, tests for detecting the antigens of the influenza virus were positive in all of these tissues.

Genetic sequencing of the virus from the cows and cats shows a high degree of similarity tying these infections epidemiologically. The authors conclude: “our findings suggest cross-species mammal-to-mammal transmission of HPAI H5N1 virus and raise new concerns regarding the potential for virus spread within mammal populations.”

Ingestion of feed contaminated with feces from wild birds infected with HPAI virus is presumed to be the most likely initial source of infection in the dairy farms. Texas is in the Central Flyway for these migratory birds that are the primary hosts and reservoirs of avian influenza. It remains unclear how cattle are transmitting the virus to other cattle, if such transmission is occurring as suspected (due to the spread of infection in herds in other states after cows were moved from one of the Texas dairy farms with an outbreak to these dairy farms).

The authors conclude with this statement: “The recurring nature of global HPAI H5N1 virus outbreaks and detection of spillover events in a broad host range is [sic] concerning and suggests increasing virus adaptation in mammals.”

• Confirmed outbreaks are now in 9 states: Texas, New Mexico, Colorado, Kansas, Idaho, South Dakota, Michigan, Ohio and North Carolina.

• At the beginning of  last week, the U.S. Department of Agriculture (USDA) announced that it will begin testing of ground beef in states with bird flu outbreaks, and recently warned the virus may be passing back and forth between cattle and poultry farms. 

• Another concerning development has been to see very sharp increases in influenza A in wastewater testing form a number of geographically distributed sites in the U.S. this month. At this time of the year, seasonal infuenza A should be well on its way down approaching low levels. Therefore, to see sharp increases raises concern that the influenza A being detected is A(H5N1) avian influenza as opposed to the seasonal human influenza viruses. Unfortunately, much of the sequencing that was being done during the COVID-19 pandemic, is no longer being done. The study: Detection of hemagglutinin H5 influenza A virus sequence in municipal wastewater solids at wastewater treatment plants with increases in influenza A in spring, 2024 | medRxiv provides us with insights. For this study, the investigators developed a PCR test to identify the H5 protein of avian influenza. They then took samples of wastewater from the time of the increases in influenza A from three of these facilities, and all three were positive for H5 and the test positivity correlated with the rise in the recent wastewater influenza A surges. The plants were located in a state with confirmed outbreaks of highly pathogenic avian influenza, H5N1 clade 2.3.4.4b, in dairy cattle. Concentrations of the H5 gene approached overall influenza A virus gene concentrations, suggesting a large fraction of the influenza A detected were H5 subtypes. At two of the wastewater plants, industrial discharges containing animal waste, including milk byproducts, were permitted to discharge into sewers.

I am going to end Part III of this update with a summary of key points from an excellent article: “A comprehensive review of highly pathogenic avian influenza (HPAI) H5N1: An imminent threat at doorstep.” https://www.sciencedirect.com/science/article/pii/S1477893923000984

1. In the recent past, the world has identified HPAI transmission involving three strains: H5N1, H5N8 and H7N9. Of these three, H5N1 is considered to be the most pathogenic, with a high mortality rate in chickens (as is required for an influenza virus to be considered highly pathogenic), but also in humans.
2. The first identified outbreak of H5N1 was among poultry in Scotland in 1959. The first known transmission of this virus to a human was in 1997 in Hong Kong. In that year, a total of 18 persons were infected, and six of them died- i.e., a case fatality rate of 33%.
3. The first recognized transmission of the virus to non-human mammals was in 2021 to foxes. However, from late 2021 on, there have been concerning spread of the virus to an ever-expanding range of animal species and increasing numbers of infections within those species. Unfortunately, the wider geographic range of infections and the involvement of new species create opportunities for the emergence of new and potentially more dangerous variants of the virus. Further, the easy transmission observed between certain mammalian species, such as Spanish minks and Peruvian sea lions, raises concern about the potential for the virus to establish reservoirs in different animal populations and pose ongoing risks to both animal and human health
4. Influenza A viruses are carried by wild birds in their intestinal tract and can be shed by these birds through various means, such as saliva, feces and nasal secretions. Transmission of HPAI H5N1 resulting in human infection primarily occurs through direct contact with infected birds.  
5. HPAI H5N1 is not efficiently transmitted to humans, however, if a pregnant woman is infected, the virus can cross the placental barrier to infect the fetus.
6. The current outbreak has seen a higher number of bird and mammal species being infected compared to previous outbreaks. This expanded range of hosts increases the potential for the virus to persist, evolve, and potentially cross species barriers, posing a threat to both animal and human health.
7. The incubation period is short, averaging 2 – 5 days.
8. In humans, as well as what has been observed in many of the mammalian species infected, after respiratory tract illness, neurologic involvement and manifestations are most common. In one study: “Out of 57 live mammals found to be infected, 53 had neurological symptoms, such as seizures, problems with balance, tremors and a lack of fear of people.” Bird flu may be making foxes and other animals behave in unusual ways | New Scientist (archive.ph)
9. In humans, severe disease results in hospitalization with complications such as adult respiratory distress syndrome (ARDS), respiratory failure, kidney failure, and an exaggerated immune response with elevated cytokines and chemokines resembling cytokine storm.

Part IV of this update is coming soon.

Part II

This is the second part of an update on the outbreaks of HPAI A(N5H1) in at least 33 dairy farms in eight states.

I am going to try to explain some very complicated matters in simple terms, so I will apologize in advance to all the cell biologists, microbiologists, virologists, anatomists, laboratory scientists and all other experts who know more than I do for my oversimplifications.

Developments

1. On April 25, the FDA reported preliminary results its nationally representative commercial milk sampling study. The initial results show about 1 in 5 of the retail samples tested are quantitative polymerase chain reaction (qPCR)-positive for HPAI viral fragments, with a greater proportion of positive results coming from milk in areas with infected herds.

[Translation: I reported in Part I of this update that the avian influenza virus has been identified at high levels in the milk of infected cows. The USDA is working with dairy farms to isolate sick cows from the rest of the heard, since we still as of this time are not certain how the virus is transmitting to and potentially among cattle. Their milk is also being discarded until such time as they are fully recovered. But questions remain, including could there be infected cows that were not showing signs of illness and yet virus might be in their milk and processed for human consumption? (The answer to this question appears to be yes.) Even if that happened, the USDA and FDA had indicated that based on what we know about influenza viruses (they are heat sensitive) and what our past experience and research has taught us about the pasteurization process (highly effective at preventing the transmission of bacteria and viruses to humans) that the milk supply should be safe and so long as the milk and other dairy products were pasteurized prior to consumption, there should be little, if any, risk to the public. However, we do not have previous studies on the effectiveness of pasteurization on this particular virus, so I applaud the USDA and FDA for designing the studies to ensure that the A(H5N1) virus is not getting into the commercial milk distribution in a potentially infectious form.

To this end, the FDA sampled commercial milk products initially with a screening technology – the use of “quantitative polymerase chain reaction” tests, tests that are much more familiar to the general public now because of the COVID-19 pandemic. So, what is this test and what does it tell us?

We can identify the presence of virus or parts of virus through looking for genetic sequences that are unique or highly characteristic of that particular virus. The genetic code for a virus, for animals, and for humans is expressed in RNA (as is the case for influenza and SARS-CoV-2) or in both DNA and RNA for some other viruses, animals and humans. That genetic material is referred to as a code because it is a sequence of building blocks called nucleotides that are limited in number (and have one variation between DNA and RNA), that are assembled in a specific order and sequence. Thus, if we were to write out that sequence of nucleotides using the initials for the various nucleotides, you would get a string of letters that is the code that serves to instruct parts of the cell that read that code what building blocks (called amino acids) should be assembled in what order that will create the proteins to make new virus, such as the H5 hemagluttinin protein and the N1 neuramidinase protein. But, when we take a sample, like you likely had if you got sick and doctors were trying to decide whether you had COVID-19 (this is different from the rapid antigen home tests), we can put it in a machine that will use an enzyme called polymerase to copy the genetic sequence and each cycle it goes through, it makes more copies of that genetic sequence until such time as the probes we use looking to see if that specific sequence is in the sample can detect it. (Another name we use for this test is NAAT – nucleic acid (that’s what nucleotides are made up of) amplification test). If the test is positive, that unique or highly suggestive specific sequence of genetic material is detected, making it highly likely that virus, or at least portions of the virus, are present in the sample. If negative, it is highly unlikely that the virus is present, at least not at levels that we can detect.  

The “quantitative” part of the test refers to that we can count the cycles of amplification of the genetic material that are necessary to get enough genetic material for us to detect. Therefore, a low number of cycles (we call these cycle thresholds or CT values) until a positive test means that there must have been a lot of virus present, because we didn’t have to amplify it much, whereas a high CT value means there wasn’t very much viral genetic material present because we had to repeatedly amplify it to get enough genetic sequences that we could detect it.

So, a negative test is the end of the story. We can be fairly confident that the virus is not present because we can’t find any of its genetic material. On the other hand, a positive test only means that the genetic material is detected, but doesn’t necessarily indicate that intact virus is present, or even if it is, that it is infectious. For example, imagine I was cutting vegetables and slipped with the knife and cut off a chunk of one of my fingers. I then took it to the hospital to see if they could reattach it. They decide they can’t, so they bandage me up and I go home. If they sent the chunk of my finger to the lab and did genetic sequencing test on the tissue, it would be my unique genetic sequence, but it would not be me. I would already be at home trying to gin up some sympathy from my wife.

Similarly, if there was virus in the milk at the farm when the cow was milked, but the pasteurization process inactivated all of the virus, and we tested a sample of milk from the grocery store that contained milk from that cow, the qPCR test might very well be positive because it is detecting the genetic sequence, but it is inactivated virus or viral debris.

So, if the genetic material is detected in the milk from the grocery store, how do we know whether the virus is intact and infectious? There is more than one way to answer that question, but the gold standard (best test) for an influenza virus, especially an avian influenza virus, is to inject some of that sample into eggs and see if it will grow (i.e., an infectious virus will infect cells of the egg, enter those cells, hijack the cell’s normal protein-making machinery and instruct it to drop everything and make viral proteins according to the instructions of the genetic material making up the virus’ RNA to make H5, N1 and all the other proteins necessary for new viruses, as well as the instructions as to how and in what order the proteins should be assembled so that new virus progeny can now exit the cell and infect new cells to repeat this process. If the amount of virus grows then we know it is replicating (infectious) virus; if it doesn’t, then it is not replicating and therefore not infectious.

This test takes days to weeks, but we are told that initial test results have not demonstrated infectious virus. If the cultures continue to remain negative, then that means that the pasteurization process is inactivating the virus, and the public need not worry about the safety of pasteurized milk for human consumption. Of course, all of this presumes that humans can be infected with A(H5N1) through ingestion, and we don’t know that for certain, though there is reason to be concerned that could be possible. (More on this below).

• On April 26, the FDA, together with the USDA, provided another update in which they reported that the embryonated egg viability studies (the scientific name for the tests I just described above using eggs to determine whether the detection of genetic material in pasteurized milk represents infectious virus or viral debris from the inactivation of virus through pasteurization). They indicated that all tests remain negative to date. We want to give these tests more time to be sure, but this is certainly encouraging news.

• There was more good news shared in that latest update. The FDA has also tested retail powdered infant formula and powdered milk products marketed as toddler formula. All PCR tests were negative, meaning that there was no genetic material from A(H5N1) detected, and therefore, no need for additional testing.

• Further, the CDC indicated that there have been no further human infections detected since the initial case identified in association with these dairy farm outbreaks. This is great news, however, to my knowledge the epidemiological surveillance is limited to persons presenting with illness compatible with influenza infections, including conjunctivitis at emergency rooms and hospitals, so we may be missing cases without broader testing and surveillance.

So, lots of good news supporting the likelihood that the pasteurization process does protect us from infectious A(H5N1) virus in that milk or dairy product. I use the word “supporting” instead of “proving,” simply because I am not sure that the embryonic egg viability studies have been given enough time to ensure that there is no growth.

Of course, all of this is moot if the A(H5N1) can’t infect humans through ingestion of virus either because the acidic environment of the stomach (of course, if this was the only protection from ingested virus, this would still leave some humans vulnerable due to hypochlorhydria (low levels of acid in the stomach) or achlorhydria (absent levels of hydrochloric acid in the stomach), conditions that can be caused by people taking antacids or proton pump inhibitors for treatment of gastroesophageal reflux or peptic ulcers, hypothyroidism, certain autoimmune syndromes, or those who have undergone surgical removal of the part of the stomach that produces acid such as those who underwent gastric bypass surgery for weight loss or a Whipple’s procedure for pancreatic cancer.) or because we do not have the right receptors lining our gut for the virus to attach allowing the virus to ultimately enter the cells and cause infection.

It seems strange to talk about ingesting an influenza virus and becoming infected because influenza virus has traditionally been spread by airborne or respiratory droplet transmission, and this mode of transmission (ingestion) does not occur with our usual seasonal influenza viruses. So, why the concern about humans drinking the milk of infected cows? There is mounting concern that a number of mammals that are carnivores or omnivores have been infected by scavenging and then eating the carcasses of infected birds, or possibly other infected animals, including cats (we recently have six reported cases of avian influenza infections in cats in the U.S. and all six died), dogs (for some reason that I don’t understand, but veterinarians likely do, beagles seem to be most susceptible among the dog breeds), leopards and tigers. While, it seems likely that ingestion is the route of infection, we cannot rule out that the virus was inhaled by the mammal during the process of eating the dead bird. There are also animal studies that demonstrate that ingestion of A(H5N1) virus can cause systemic dissemination of virus in these animals, e.g., see “Systemic Dissemination of H5N1 Influenza A Viruses in Ferrets and Hamsters after Direct Intragastric Inoculation.” https://doi.org/10.1128/jvi.00148-11 In this particular study, the virus was introduced directly into the stomach, bypassing the oral and nasal passages, which should eliminate the confounding risk that possibly the virus was inhaled during the process of eating.

While there are reports of people with human infections of avian influenza having conjunctivitis as the only manifestation, those who become severely ill and die have pneumonia, so there needs to be a route for the virus to get from the gut to the lungs, if ingestion is a route of transmission that can result in severe illness and death. Because there are no direct connections where virus can merely advance from cell to cell and tissue to tissue to the lungs, one would postulate that for virus to get from the gut to the lungs, it must do so either through the blood (what we would call a viremic phase in which virus enters the bloodstream and can circulate to other organs) or a lymphatic route, in other words, from the gut, to the local lymph nodes to the regional lymph nodes and ultimately into the lymphatic system.

The animal study referenced above, showed that virus could rapidly and directly infect the lymphatic system after inoculation of virus directly into the ferrets’ and hamsters’ stomachs, but in the hamster model, there was also evidence for hematogenous (by the blood) spread to the lungs. Hamsters have some particular relevance to what may happen in humans as they are susceptible to the normal seasonal influenza viruses that we get infected with, and they seem to have a similar distribution of the relevant receptors (more on this later) for the avian influenza viruses.

Here is an illustration from that article:

The infectious virus is represented in red. The results of the study suggest that when the animal ingests food containing infectious virus, the virus enters the stomach and travels through the animal’s digestive tract down to the intestines (represented in the picture by the letter a). Our intestines have lymph nodes within and adjacent to the intestines that help us respond to potential pathogens we might ingest. However, in this case, the virus is not contained by this first line of defense, first causing lymphadenitis (infection of the lymph nodes) and then spreading beyond these nodes into the lymphatic system (represented by the letter b in the illustration). The virus is transported through the lymphatic system into the thoracic duct which returns the lymph to the venous system and venous return to the right side of the heart (represented by the red arrow in the illustration). The right side of the heart pumps the venous blood that returns to it from all parts of the body, containing the lymphatic return from the thoracic duct, to the lungs, where the lungs oxygenate the blood that will then return to the left side of the heart to be pumped out to the body to deliver oxygen and nutrients to tissues. However, it is the pumping of the venous and lymphatic return (now containing virus that entered the body from the gut) to the lungs (represented by the letter e in the illustration) that transports the virus to the lungs and results in pneumonia.

Seasonal influenza viruses that humans are exposed to each year do not infect us in this manner, probably because the H1, H2 and H3 proteins do not tolerate the low pH (acidic) environment of our stomachs. However, it appears that H5 does tolerate this environment much better, and may explain why there may be a risk of infection from ingestion of avian influenza viruses in humans that is not characteristic of the seasonal influenza viruses we are familiar with. Obviously, more research is needed.

I will pick up on this update in Part III, because we still have much to cover. Dr. Rick Bright is a renowned virologist and immunologist who has been an influenza researcher for decades, who also served our country as the director of the Biomedical Advanced Research and Development Authority (BARDA). He and other scientists have raised four important questions that need to be answered about these outbreaks https://www.npr.org/sections/health-shots/2024/04/26/1247479100/bird-avian-flu-cows-cattle-milk-virus-unanswered-questions. They include:

1. How widespread is the virus in dairy cattle?
2. Does the milk testing positive on retail shelves contain infectious virus?
3. How exactly is the virus spreading?
4. What is the risk to humans as the virus keeps spreading?

I certainly don’t have the answers to these important questions, but I will continue to update the public about what we know, what we are learning, and what is happening with these outbreaks. We have a lot more to discuss in Part III of this update.