My role of trying to educate the public about this developing pandemic and the actual and potential risks that SARS-CoV-2 infection presented back in the first two years, when misinformation and disinformation were rampant, and when the evidence was still unfolding, and especially prior to the availability of vaccines, was greatly challenging.

On one hand, there was the loud voice of minimizers who likened COVID-19 to a cold or possibly even the flu and discouraged precautionary measures, and  on the other hand, but not mutually exclusive, a group of physicians with more promotion on social media, cable networks, and even some of the mainstream media, who advocated for the unhealthy and elderly to stay home, but to have children and young adults return to all their normal activities, including those known to be high-risk for infection, to promote infection with the pronouncement that our country would then achieve herd immunity and COVID-19 would no longer present a significant threat to society. One well-known and nationally renowned physician even wrote an article for a major news outlet that predicted that we would achieve herd immunity as a country by April of 2021. I tried to warn the public that that prediction was not based upon any sound facts or science and was completely unreasonable. In fact, nearly 3 ½ years later, we still have not achieved “herd immunity.” I wrote at length about what herd immunity is, what factors are necessary to achieve herd immunity, and why herd immunity was not a reasonable expectation with the SARS-CoV-2 virus, at least for the foreseeable future in our book, Preparing for the Next Global Outbreak: A Guide to Planning from the Schoolhouse to the White House, https://www.press.jhu.edu/books/title/12896/preparing-next-global-outbreak.  

Another challenge that was frustrating and challenging to deal with was the fact that the public’s and government’s focus and attention was on hospitals being overwhelmed and people dying from the disease. I tried repeatedly to raise the point that it often takes years after we first recognize a new virus to determine the long-term health consequences of infection, and sometimes these consequences can be serious and even disabling. I urged people to consider that we may learn of such health consequences from infection with SARS-CoV-2, so those who were being encouraged to take a cavalier approach to this virus because they were not in any of the identified high-risk groups, might still want to take reasonable steps to minimize the risks of infection, or at least guard against multiple reinfections, which would very likely increase any such long-term health risks. It is hard to know if my warnings made much of an impact.

Unfortunately, since then, we have learned that there are many potential long-term health risks, some that I had not even contemplated, and that these risks do, in fact, appear to increase with increasing number of infections.

In this blog post, I am only going to review two studies (more to come). The first is a study that would never be approved in the U.S. because the study took healthy individuals and exposed them (we call this a challenge study) to SARS-CoV-2 to study the effects of infection. Published by The Lancet, the investigators of this study, Changes in memory and cognition during the SARS-CoV-2 human challenge study – eClinicalMedicine (thelancet.com), took 34 healthy volunteers who had no history of COVID-19 and who were tested by serology (antibody testing) to ensure that they had no antibodies to the virus that would suggest prior asymptomatic or pauci-symptomatic infection of which the subjects were unaware, and inoculated them (introduced the virus directly into their nasal passage) with the wild type (original strain) of SARS-CoV-2. The investigators then conducted cognitive tests on the subjects (some who developed evidence of infection: measurable and sustained viral loads by PCR testing and some who did not become infected who then served as the comparison group) during their period of quarantine and at 30, 90, 180, 270, and 360 days following their artificially-induced infections in order to compare the results to their pre-infection, baseline cognitive testing. Of the eighteen subjects that developed laboratory evidence of infection, one was asymptomatic and all the others suffered only mild illness (i.e., not severe enough to require medical attention or intervention).

The infected subjects demonstrated statistically significant lower global composite cognitive scores than uninfected volunteers, and this difference occurred both during the acute infection, as well as through the follow-up period of 1 year. Memory and executive function tasks showed the largest between-group differences and this was despite the subjects generally having no awareness of the cognitive decline.

Although this was a small number of subjects tested, it was concerning that cognitive decline was detected in all cases, whether the infection was asymptomatic or mild. It remains an unanswered question as to how many of these subjects ever returned to their baseline level of cognitive functioning. While these subjects were not aware of their cognitive decline, it is not uncommon for people during and after COVID-19 to report “brain fog,” which generally refers to loss of memory, difficulty focusing, and difficulty maintaining attention for prolonged periods of time. Keep in mind that these subjects ranged in age between 18 and 30; these were not elderly individuals, but rather young adults in the prime of their lives. It also raises concern that with this impact on young adults, what is the impact on children with still developing brains?

The second study was a review article published in the New England Journal of Medicine in February of this year: Long Covid and Impaired Cognition — More Evidence and More Work to Do | New England Journal of Medicine (nejm.org). I have previously written about some of the neurologic and psychiatric sequelae of COVID-19, but this study looks further into a recent analysis of the U.S. Current Population Survey that showed that after the start of the Covid-19 pandemic, one million U.S. residents of working age reported having “‘serious difficulty’ remembering, concentrating, or making decisions” than at any time in the preceding 15 years. While in the previous paper, the investigators established cognitive decline with infection with the original strain of SARS-CoV-2 that occurred even with asymptomatic or mild infection and persisted at least a year, these authors point to the fact that cognitive decline has been reported with every variant since the original 2019 virus.

Concerningly, these researchers state:

As compared with uninfected participants (control), cognitive deficit — commensurate with a 3-point loss in IQ — was evident even in participants who had had mild Covid-19 with resolved symptoms. Participants with unresolved persistent symptoms had the equivalent of a 6-point loss in IQ, and those who had been admitted to the intensive care unit had the equivalent of a 9-point loss in IQ.

They go on to point out:

Memory, reasoning, and executive function (i.e., planning) tasks were the most sensitive indicators of impaired function, and scores on these tasks tended to correlate with brain fog. Vaccinations provided a small cognitive advantage. Reinfection contributed an additional loss in IQ of nearly 2 points, as compared with no reinfection.

It is hard to know the significance of these findings without longer follow-up and surveillance. But, these findings are concerning enough that I believe it prudent to try to protect our children is schools with better air handling, ventilation, and filtration. It is frustrating to me that minimizers, promoters of herd immunity, disinformation purveyors, and even our own public health messaging no doubt contributed to such a high population infection burden. I hope all of these changes in cognitive function reverse over time, but given that prior studies have shown that imaging can detect structural alterations to the brain, including loss of brain tissue, I am skeptical that all persons will experience recovery.

Starting tomorrow (Monday, September 23, 2024), all U.S. households can once again request 4 free at-home rapid antigen tests for COVID-19 on the website www.COVIDTests.gov.

For information about at-home rapid antigen tests, see At-Home OTC COVID-19 Diagnostic Tests | FDA.

Before throwing out tests you may have at home already, keep in mind that for many, the expiration dates have been extended beyond the date printed on the packaging. To see if your tests’ expiration dates have been extended, go to At-Home OTC COVID-19 Diagnostic Tests | FDA.

UPDATE (9/23/24)

I tried to submit my own order today, but apparently there is a delay. The government now states that you will be able to order them by the end of the month (1 week from today), but I cannot find anywhere where they specify the exact day.

One caution: Be sure you use COVIDTests.gov and not COVIDTests.com (the latter is an active website for a private company).

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.