In my last two blog pieces, I began a blog series addressing the fact that we have seen a number of diseases that are not endemic to the U.S. pop up and cause outbreaks. Some of these are infections that we have not previously seen people acquire in the continental U.S., but rather were involving international travelers who acquired the infection elsewhere, then traveled to the U.S., became ill, and were diagnosed with the illness here.

In part I, I reviewed a short history of a number of these outbreaks focusing on those that have occurred since 2020 to illustrate that this is not just one or two diseases, nor ancient history.

In part II, I discussed the dengue virus that caused an outbreak in Florida in 2020 that was of note because we rarely see locally contracted infections in the continental U.S.

In this blog piece, I will discuss the Zika virus. Zika virus belongs to the same family of viruses as the dengue virus – flaviviruses. As I mentioned in my last blog piece, flaviviruses are vector-borne diseases, meaning that instead of human à human transmission or animal à human zoonotic transmission, these viruses are transmitted through the bites of mosquitoes (although there is some evidence that Zika can be transmitted through sexual contact, blood transfusions, and perhaps even tissue or organ donation, though these are all less common routes of transmission. Nevertheless, WHO recommends that men returning from an area with active Zika transmission use protection or abstain from sex for a period of 3 months after their return to protect their sexual partners and that women engage only in protected intercourse or abstain from sex for a period of two months following their return from an endemic area). The same type of mosquito that transmits dengue virus and the Chikungunya virus also transmits Zika virus, and thus we tend to see Zika infections in tropical and subtropical regions of the world.

Zika virus was first identified in Uganda in 1947 in a Rhesus macaque monkey followed by evidence of infection and disease in humans in other African countries in the 1950s. During the 1960s through the 1980s, Zika disease predominantly occurred in Asian and African countries. since 2007, outbreaks of Zika virus disease have been recorded in Africa, South and Central America, Asia and the Pacific rim countries that are in the southern hemisphere, where the Aedes mosquitos abound.

In 2015 and 2016, large outbreaks of Zika virus occurred in Central and South American countries, resulting in an increase in travel-associated cases detected in US states, and widespread transmission in Puerto Rico and the US Virgin Islands. In July of 2016, the first outbreak in the continental United States was identified in the Wynwood area of Miami-Dade County, Florida.

While like dengue fever, most cases of Zika virus disease are mild, in early outbreaks we observed an increased frequency of Guillain-Barre’ syndrome (GBS), a disorder that can range from a brief duration of mild weakness and abnormal sensation, to an ascending paralysis that can be severe and progressive enough to require a ventilator for respiratory support until the condition resolves, which it does in most cases. GBS can evolve rapidly over hours, or more slowly over days or even weeks.

When Zika emerged in the Americas with a large outbreak in Brazil in 2015, we noticed an alarming association between Zika virus infection in pregnant women and congenital microcephaly (an abnormally small head) of the infants delivered from these mothers. Infants with complications from their mothers’ Zika infection during pregnancy are said to have congenital Zika syndrome. This appears to occur in 5 – 15% of pregnancies during which the pregnant mom becomes infected (some reports are as high as one-third of infants born to mothers with Zika infection during pregnancy will develop microcephaly), even when the mother is completely asymptomatic and unaware that she was infected. Besides the microcephaly that is generally quite obvious and devastating on its own, this syndrome can include limb contractures (where the arms or legs are unable to move the full normal range of motion), abnormal muscle tone, eye abnormalities and hearing loss. Also tragically, some babies will become non-viable and the mother will experience fetal loss or the baby may be a stillbirth. Zika infection during pregnancy can also result in premature birth.

There is a study following the infants born with congenital Zika syndrome in Brazil following the large outbreak in 2015 that shows these infants have an 11-fold higher mortality risk during the first year of life.

Like with dengue fever, most persons who are infected with Zika virus do not develop symptoms or develop only mild symptoms. Those that do become symptomatic generally do so between days 3 and 14 following infection. Many of the symptoms are similar to those of dengue fever – headache, fever, muscle and joint pain and rash. The symptoms generally last 2 – 7 days.

Other complications of Zika virus disease tend to occur in older children and adults and include Guillain-Barre’ Syndrome (discussed above), peripheral neuropathies (loss of proper nerve functioning of one or more nerves to the extremities), or myelitis (an inflammation of the spinal cord).

Like dengue fever, there are no specific treatments or therapies for Zika virus disease; but unlike dengue fever, there is no vaccine against Zika.

Again, there is nothing in particular that Americans need to do in regard to Zika unless you are planning to travel to an endemic area, however, our public health planning needs to take into account these increasing occurrences of outbreaks of vector-borne diseases occurring in the southern U.S. that we have not previously dealt with in terms of locally acquired infections.

We have had outbreaks in 2016 (Zika), 2020 (dengue fever) and 2023 (malaria). We must consider these as warning signs. In my next blog post, we will discuss Chikungunya.

In my last blog piece, I wrote that we have seen a number of diseases that are not endemic to the U.S. pop up and cause outbreaks. Some of these are infections that we have not previously seen people acquire in the continental U.S., but rather were involving international travelers who acquired the infection elsewhere, then traveled to the U.S., became ill, and were diagnosed with the illness here.

Dengue virus is endemic to over 100 countries in the southern hemisphere, predominantly those in tropical and subtropical regions of the world. While we do occasionally see outbreaks of dengue fever in the U.S. territories of American Samoa, Puerto Rico, and the U.S. Virgin Islands, and the freely associated states, including the Federated States of Micronesia, the Republic of Marshall Islands, and the Republic of Palau, cases in the continental U.S. have historically been in international travelers or travelers from these territories.

In 2020, there was an outbreak of locally-acquired dengue fever in Florida (72 cases), which might be less of a concern if it were not for the pattern of emerging outbreaks of other diseases for which we generally have not seen locally acquired infections in the past, but now have resulted in local outbreaks, especially in Florida – e.g., zika, chikungunya prior to the dengue fever outbreak and most recently malaria (while we have historically had local transmission of malaria, we had eliminated malaria from the U.S. back in 1951). It is interesting to note that the common denominator for these four infections is that they are all transmitted through mosquito bites.

Dengue virus is a flavivirus and flaviviruses cause vector-borne diseases in humans. Vector-borne means that the virus is transmitted to humans through the bite of an insect – typically a mosquito, flea or tick. Dengue virus is transmitted by mosquitoes. Other mosquito-transmitted flaviviruses include the yellow fever virus, Japanese encephalitis virus, the West Nile viruses, and Zika virus.

The mosquitoes that are capable of transmitting dengue virus are of the Aedes species. Modelling studies show that Aedes aegypti and Aedes albopictus mosquitoes could potentially extend their natural habitats in the southern hemisphere up to some areas of the U.S., particularly the southeastern parts of the country.

We may miss cases of dengue fever in the U.S., because in some people (estimated to be about 75% of cases), the illness is mild or even asymptomatic. Those with mild symptoms may attribute them to a cold or the flu, or be seen, but not tested for dengue fever given that this is not something most U.S. doctors have seen before.

Dengue fever can manifest as a severe disease, in fact, it is estimated that 22,000 people die from dengue annually across the globe. Classic dengue fever is characterized by high fever and intense muscle, joint and bone aching, and even muscle spasms, giving rise to its colloquial name, “breakbone fever.”

In classic dengue fever, the first phase of the illness lasts 2 – 7 days. In addition to fever and the muscle, joint and bone pain, some patients will complain of headache, nausea and vomiting and some may experience bruising, bloody nose, or bleeding from their gums. On or about the third day of the illness, most people who are symptomatic with dengue will develop a red rash, that may be smooth, may have tiny bumps, or both. In most cases, the rash does not itch. Some patients will get a rash all over their body, while others will have patchy rashes. When the rash is generalized, it generally begins over the tops of the feet and the back of the hands and then spreads to the arms, legs, abdomen and chest. There is much variation in the possible rashes and in some cases, the particular manifestation of rash tells us what the major underlying pathological process is (e.g., immune reaction versus disruption to the proper functioning of the blood and blood clotting system).

While most people recover within about a week, some people do deteriorate and require hospitalization (about 1 out of every 20 cases). Those at highest risk for severe disease are infants, pregnant moms and those with a reinfection of the virus. They can experience profound fluid losses or maldistribution of these bodily fluids, internal bleeding (sometimes called dengue hemorrhagic fever) and potentially can develop shock (sometimes referred to as dengue shock syndrome).

While many lay people are under the false impression that the initial infection of any illness is the worst, and that subsequent infections will always be milder, this is not always the case, and dengue fever is the classic exception. In the case of dengue reinfections, a phenomenon called antibody-dependent enhancement (ADE) can occur. In essence, what takes place is that the initial infection triggers an immune response. Part of that response is the production of antibodies against the virus. When non-neutralizing antibodies are produced (e.g., antibodies that attach or bind to the virus, but do not interfere with or prevent the virus from entering and infecting cells), there are some cases in which these weak antibodies can actually promote the viral cell entry and infection, often also stimulating an intense inflammatory process, a condition we refer to as ADE.

There is no specific treatment available for treating dengue fever. The efforts to develop a vaccine against this infection has been hampered by the potential for ADE. However, there is a vaccine, though it is not licensed in all countries where dengue virus is endemic.

For now, Americans need not take any specific precautions unless you are planning travel to countries where dengue is endemic. However, we need to be mindful of our own changing and evolving public health situation in the U.S.

With climate change, we may see more and more diseases that are not endemic in the U.S. migrating northward. Further, if we continue to exercise a great deal of complacency against other disease outbreaks in the U.S. such as SARS-CoV-2 and monkeypox, we risk allowing these diseases to become endemic, especially, as we allow new variants to emerge and allow infections to transmit among our wildlife and domesticated animals. We often have an opportunity to eliminate infectious diseases, but that window does not stay open for indefinite periods of time. Further concerning is the fact that after going to the efforts to eliminate a number of vaccine-preventable illnesses in the U.S., we have allowed these diseases to reemerge in outbreaks due to the uncontrolled misinformation, disinformation and anti-vax campaigns that are undermining vaccine confidence in the U.S. and globally.

It should be concerning to everyone that is paying attention that we are experiencing disease outbreaks in the US of diseases that we generally shouldn’t see outside of international travel. In some cases, these are the emergence of diseases that are endemic to other countries of the world, but not the US, and frustratingly, others are the resurgence of diseases that we previously eliminated from the U.S. Consider the list of these diseases in just in the past three years (if we went back further, we could add other infectious diseases to the list such as zika and chikungunya):

2020 – SARS-CoV-2 (novel virus)

              Dengue fever (endemic in the southern hemisphere)

2022 – Monkeypox (previously endemic to only African countries)

              Polio (eliminated from the US in 1979)

              Candida auris

              Measles (eliminated in the US in 2000)

2023 –   Malaria (eliminated from the U.S. in 1951)

The reasons are many, including:

1. The world is failing to appreciate that infectious diseases that appear limited to poor and developing countries are a threat to all countries given international travel and trade (including wildlife).
2. The world is not investing enough in research of novel viruses, antiviral development and better vaccines (durability and the induction of mucosal immunity) with broader coverage against families of viruses that pose epidemic and pandemic threats.
3. The world is not doing enough to minimize the risks of zoonotic (animal à human) transmission of novel viruses. It is estimated that roughly 75% of all newly recognized infectious agents are the result of these spillover events to humans.
4. Climate change and the resulting geographic changes in habitats of animals and vectors (e.g., mosquitos and ticks) that transmit infections to humans.
5. The rampant spread of medical misinformation and disinformation, including the well-organized, well-coordinated and well-funded antivax campaign, that has undermined vaccine confidence, and as a result, vaccination rates, is leading to a resurgence in vaccine-preventable diseases.

I have already written extensively about SARS-CoV-2 previously, so in my next blog post, I will cover Dengue fever and subsequently, the other diseases on this list.

If we were to ask Americans what disease outbreaks the world has experienced in the past 3 years, I suspect almost everyone would be able to identify COVID-19 (caused by the SARS-CoV-2 virus). Probably a large number, but certainly less would also be able to name influenza, likely by using its colloquial name of the “flu.” My guess is that if we pressed for more, a minority of Americans would be also able to identify RSV (respiratory syncytial virus) and possibly monkeypox (recently renamed by the CDC as MPox). I would be impressed if more than a handful of people would be able to recall the health alerts in the U.S. for Candida auris, drug-resistant gonorrhea, increased rates of syphilis, the drug-resistant bacterial infections (Pseudomonas aeruginosa) with artificial tears and eye drops, the outbreaks of norovirus, the hepatitis of unknown etiology in children, or the most recent outbreaks of malaria in Florida and Texas. I suspect that no lay person would realize that we had a larger than usual outbreak of human metapneumovirus infections at the beginning of this year and into the spring, unless they were one of the many infected with this virus.

Of course, there have been many more outbreaks than this that have received relatively little attention in the media and press, including outbreaks that we have had in the U.S., specifically polio in New York and measles in Ohio.

Among the many other outbreaks that occurred in parts of the world such as Marburg virus disease and Lassa fever, there was one that really caught my attention and caused me to do a double-take, and yet, I doubt any one other than infectious disease experts, public health experts or virologists knows anything about this virus.

In August 2022, a novel henipavirus named Langya virus caused an outbreak in China among 35 farmers and local residents that likely contracted the infection from shrews. The virus was isolated from patients with severe pneumonia. We already knew about two other henipaviruses – Nipah virus and Hendra virus. The case fatality rate for henipavirus infections in humans is approximately 70%. Hendra virus was first identified in 1994 in specimens taken mostly from horses, but also some humans with respiratory and neurologic disease in Australia. The source of the virus is flying fox bats (aka fruit bats). Hendra virus is not of significant pandemic concern because the virus primarily infects horses and humans are generally only infected by contact with the secretions or tissues of infected horses. Further, no human-to-human spread has been identified.

Nipah virus is a different story. Nipah (pronounced “Nee-paw”) is also transmitted by fruit bats, but it infects humans and pigs. It can cause inflammation and swelling of the brain, a condition doctors refer to as encephalitis. The illness can range from mild to severe, including death. Outbreaks have historically occurred in India and Bangladesh.

Nipah virus presents more of a potential pandemic threat than Hendra virus because while the earliest outbreaks appear to have resulted from transmission from bats à pigs à humans with little, if any, human-to-human transmission, human-to-human transmission regularly occurs in more recent outbreaks. Close contact with a person with Nipah virus disease can cause transmission through body fluids – nasal secretions, respiratory droplets, blood and urine. Transmission most often occurs within families and within health care settings.

However, Langya virus presents more a of potential pandemic threat in my mind than the other henipaviruses for the following reasons:

• The first known spill-over event was in August of 2022. (In case you don’t understand why that would increase the pandemic threat relative to the other two viruses in its family – Hendra and Nipah viruses – it is because the other two viruses have been circulating in the animal and human population much longer, and therefore, have already had more opportunity to develop more efficient transmission in humans and to have caused a major outbreak by now, but haven’t yet.
• Rats and shrews can serve as intermediate hosts for Langya virus and are distributed globally, which greatly increases the risk of infections in humans, as people living in large metropolitan areas are far more likely to encounter rats than pigs (Nipah virus) or horses (Hendra virus).
• The fruit bat is migratory, which means that it can carry the virus with it to new geographic areas.
• The Langya virus is a novel and antigenically distinct from its cousins, Nipah and Hendra viruses, which means that there is no significant pre-existing immunity, nor is there likely much cross-over protection (in other words, antibodies to Nipah virus are unlikely to be protective against Langya virus.

What this means is that we need to conduct more research into these novel viruses to better understand their pathogenesis, to develop treatments and hopefully develop effective vaccines.

I have been preparing for pandemics for more than two decades in my roles as a leader of a major teaching hospital in the Texas Medical Center and subsequently as the President and CEO of the largest health system in Idaho.

In pandemic planning, I have found it useful to consider past outbreaks, epidemics and pandemics to consider which pathogens were not eliminated and have the potential to recur. For example, I didn’t spend much effort worrying about smallpox (the only virus we have eliminated from the world as a natural infection) because the only way we would see that would be as a result of a state-sponsored bioweapon attack. I also crossed the original SARS virus (2003) off my list because to our knowledge, that virus never was introduced into an animal reservoir before we contained the spread of the outbreak in humans (very much unlike what has happened with the second SARS virus – SARS-CoV-2 (2019). Further, while we still have cholera outbreaks in the world, they tend to be isolated to locations without proper water treatment and in locations following natural disasters that lead to flooding and disruption of the infrastructure. Further, person-to-person transmission of cholera is minimal and unlikely to propagate the spread to other areas of the world.

We must keep in mind that the majority of emerging infectious diseases in humans are the result of zoonotic transmission (animal à human). More than 70% of these pathogens arise in wildlife.

Looking a past epidemics and pandemics, the pathogen that would rise to the top of the list for causing a new pandemic would be an influenza A virus with zoonotic transmission to humans and mutations that would increase its virulence as well as its efficient spread from person-to-person. That has happened three times in the 20^th century – 1918 (the so-called Spanish flu – H1N1), 1957 (the so-called Asian flu- H2N2), and 1968 (the so-called Hong Kong flu- H3N2). Currently, we are watching the alarming spread of H5N1 avian influenza among multiple species of mammals causing significant mortality. Normally, there is a genetic protection of humans from these avian viruses, however, with increasing transmission among mammals, the potential for significant mutations (specifically, influenza viruses tend to develop the most profound genetic modifications from reassortment of their genes – a swab of genes from one virus to another), is concerning for the potential to develop a new mechanism by which the virus can infect humans with better onward human-to-human transmission.

As I wrote in Preparing for the Next Global Outbreak, https://www.press.jhu.edu/books/title/12896/preparing-next-global-outbreak, we must expand our readiness and preparedness for novel viruses as:

• the frequency of human-wild animal interactions increases with:
  • human expansion into wild animal habitats;
  • wet markets continue to operate in various countries;
  • non-domesticated animals are exported for research purposes or as part of black-market trade; and
  • the world becomes increasingly interconnected through international travel.

In addition, we must also anticipate diseases showing up in the US that were previously endemic only to poor and developing countries due to the increase in international travel. One example was the case of a man who traveled from an African country to the U.S. with Ebola virus disease who developed symptoms once he was in the U.S. and subsequently presented to a hospital in Dallas on September 25, 2014. This one patient had 48 contacts, 6 of whom would be considered close contacts, prior to his death from Ebola. Two nurses caring for this patient before he was diagnosed became infected. Ultimately, 147 health care workers were involved in the care of the initial patient and the two infected nurses. It is easy to see from this how one person can potentially expose many people if the person is not so sick as to be incapacitated or the disease has not been identified and people are not using proper protection. Just last year, we had another wake-up call. Monkeypox was first identified in 1958. There have been outbreaks of disease in humans since 1970, primarily in African countries. With lack of appreciation of the global risk presented by novel viruses that first appear in low income and developing countries, the world largely ignored these outbreaks and did little to study the virus, to develop antiviral treatments and to develop vaccines. Then, in 2022, a global outbreak with monkeypox developed.

Finally, health care leaders must also consider diseases endemic to countries in the southern hemisphere that may now present in the U.S. due to climate change (e.g., Chikungunya outbreaks in Florida and Texas in 2014 and Zika in 2015 and 2016, and malaria in 2023).

For the past three years, I have been warning that SARS-CoV-2 (COVID-19) will not be our last pandemic. Just in the past two decades we have had an epidemic or pandemic with novel viruses at intervals of 6 years, 3 years, and 7 years.

The World Health Organization prepared a list of pathogens that it considers to pose the highest risk for a future outbreak or potentially, a pandemic in 2018. That list turned out to be quite prescient (as you can see that outbreaks with almost every virus listed have occurred since then) and contains the following infectious diseases:

• Crimean-Congo hemorrhagic fever (there is currently an outbreak in Afghanistan involving more than 100 people, with 6 deaths reported so far);
• Ebola virus disease (there was an outbreak from September 20, 2022 until January 10, 2023 in Uganda with more than 160 people infected, 77 of whom died);
• Marburg virus disease (an outbreak was declared on 2/13/23 in Equatorial Guinea. It infected 16 people, 12 of whom died. It was contained and declared over on May 15, 2023);
• Lassa fever (there have been outbreaks in Nigeria and in Ghana. The outbreak in Ghana began in February 2023 and was contained rapidly with no new cases since March 2023, with 27 people in total infected, one of whom died);
• Middle East respiratory syndrome (MERS) (there were three cases reported between December 2022 and May 2023, involving 1 death);
• Nipah virus disease (between January 4, 2023 and February 13, 2023, there have been 11 cases resulting in 8 deaths in Bangladesh);
• Rift Valley fever (there was an outbreak in Mayotte, France between November 2018 to July 2019 involving 142 confirmed cases); and
• Zika (in March 2015, Brazil reported a large outbreak that was soon thereafter determined to be Zika virus disease. In 2015 and 2016, there was widespread transmission of Zika in Puerto Rico and the U.S. Virgin Islands, as well as limited local transmission in Florida and Texas. Only counting cases that were locally acquired (not cases in travelers from other countries to the U.S., between 2015 and 2017 when the last case occurred in the continental U.S., there were a total of 231 cases in the continental U.S. and 37,041 cases locally acquired in U.S. territories (Puerto Rico and US Virgin Islands).

I have never advocated for living in fear. But, worse, in my opinion, is living in ignorance. I believe in doing risk assessments and then prioritizing those risks based upon the likelihood of the threat coming to pass versus the magnitude of harm that would result if the risk materialized. I illustrate how to do this and make decisions based upon this assessment on pages 277 – 280 in the book – Preparing for the Next Global Outbreak.

Fortunately, some of the viruses with the highest mortality rates (70+%) are less likely to cause pandemics than other viruses with lower mortality rates. However, that is for viruses that we know about today, and even if that were still the case for all new emerging novel viruses, there are still plenty of viruses that have mortality rates 10 – 20 times what we saw with SARS-CoV-2 that under the right circumstances could efficiently spread and cause a pandemic.

We must increase our surveillance, improve our response to outbreaks and promote cooperative international research into passive immunity treatments, vaccines that can provide durable, mucosal immunity; antiviral therapies that are effective against an entire family of viruses; rapid and inexpensive tests for these viruses that can be rapidly deployed, and research to identify the main antigenic targets for each of these vaccines that might allow for the rapid development of effective vaccines.

There has rightly been a lot of focus on bats, particularly in southern China and in Saudi Arabia because 3 novel coronaviruses capable of causing severe acute respiratory syndrome have been identified in those countries in the past 20 years – SARS-CoV (2003) – China, MERS-CoV (2012) – Saudi Arabia and SARS-CoV-2 (2019) – China. We know that bats often carry coronaviruses and that we have only yet begun to sample and characterize al the coronaviruses they carry and can transmit to animals such as palm civets, raccoon dogs, camels, pangolins, and many others that can then serve as potential intermediate hosts for zoonotic transmission to humans.  A major route of transmission of coronaviruses from bats to animals is thought to be through fruit. The bats feast on fruit and in doing so can contaminate the fruit with coronaviruses, or alternatively can contaminate the ground with coronaviruses passed through their guano (excrement). The partially eaten fruit often falls to the ground, where animals, such as those mentioned above, forage for food, eating the residual fruit or ingesting the guano-contaminated vegetation exposing themselves to coronaviruses left by the bats.

Recently, researchers have reminded us that not all worrisome coronaviruses will necessarily arise out of Asian or Middle Eastern countries. A team of researchers from the Imperial College of London and the University College of London sampled 48 fecal specimens from 16 of the 17 species of bats that reside in the UK.

From these 48 specimens, they recovered 9 whole coronavirus genomes (i.e., a complete copy of their genetic material), which allows for identification of the coronavirus. Coronaviruses are divided into 4 genera based upon certain biological characteristics– alpha- and beta-coronaviruses infect mammals and gamma- and delta-coronaviruses primarily infect birds, but there is a gamma-coronavirus that infects whales and a delta-coronavirus that infects pigs.) Of these 9 coronaviruses:

• 4 were alpha-coronaviruses (you may recall my earlier blog piece discussing human coronaviruses in which I indicated that common cold coronaviruses 229E and NL63 are alpha-coronaviruses)
• 5 were beta-coronaviruses:
  • One was a merbecovirus – (the sub-genus to which MERS-CoV belongs)
  • 4 were sarbecoviruses, which are in a sub-genus to which SARS-CoV and SARS-CoV-2 belong. At least one of the novel sarbecoviruses can bind the ACE-2 receptor to infect human cells as SARS-CoV-2 does, though it does so sub-optimally. In addition, these sarbecoviruses were only one mutational step away from a development (a furin cleavage site) that would significantly enhance virus receptor binding and potentially infectivity. (Note that it was the fact that SARS-CoV-2 did have a furin cleavage site that many used to justify that SARS-CoV-2 was genetically engineered or modified, but this (and other findings) demonstrate that a furin cleavage site can be a result of natural viral evolution.)

2 of the coronaviruses identified were previously unknown coronavirus strains – i.e., novel coronaviruses (one of the alpha-coronaviruses and the merbecovirus).

The key takeaways are these:

1. There will continue to be future outbreaks, epidemics and even pandemics.
2. Outbreaks that occur anywhere in the world threaten every other part of the world due to international travel and trade.
3. Most new, emerging infectious diseases are zoonotic in origin (transmitted by animals to humans).
4. Increasing human expansion into wildlife areas is increasing the risk for zoonotic events.  
5. Climate change is causing introductions of infectious diseases into some more northern geographic locations where these infectious diseases had previously not been circulating.

We must prepare now. For a full discussion of preparation see Preparing for the Next Global Outbreak, https://www.press.jhu.edu/books/title/12896/preparing-next-global-outbreak. Preparation includes increased surveillance, improvement in our response to outbreaks and promotion of cooperative international research into passive immunity treatments; vaccines that can provide durable, mucosal immunity; antiviral therapies that are effective against an entire family of viruses; rapid and inexpensive tests for these viruses that can be rapidly deployed, and research to identify the main antigenic targets for each of these vaccines that might allow for the rapid development of effective vaccines.

If you would have asked me this question a year ago, I would have said that I think it is one of two likely answers: (1) it might, but I suspect it will be a relatively minor contribution among a whole host of factors that determine your risk, or more likely, (2) it is not actually your blood group, but rather another genetic factor determined by a gene that is in close association with the gene that determines your blood group. We have been seeing what appeared to be a correlation between your ABO blood group and risk for infection since early on in the pandemic, but we have simply not known whether that is just an association or if it is causation, and if the latter, how would your ABO blood type impact infection risk?

A recent study (Blood Group A Enhances SARS-CoV-2 Infection | Blood | American Society of Hematology (ashpublications.org)) provides us with an answer, and it appears that at least my second potential answer was wrong.

A quick refresher. Most of you will have heard of blood groups, and perhaps you are a regular blood donor and know your blood group. You also likely know that your blood group is genetically determined in that your biological family members have a limited number of possibilities for their blood group based upon your own, and you may be aware that in the past, blood group was one of the things looked at in paternity cases (it can’t prove paternity, but it can rule it out).

The prevalence of blood groups among Americans from most common to least is: O+ (roughly 38%of the population), A+, B+, O-, A-, AB+, B-, AB- (roughly 1%). The positive or negative sign that follows your ABO group is your Rh factor, and we are not going to get into that for purposes of this discussion. I qualified that these prevalence numbers are for Americans, because the prevalence of blood groups will vary among different racial and ethnic populations. Even within the U.S. population, the prevalence of blood group varies by race and ethnicity, e.g., 43% of Caucasians are blood group O, but only 28% in the Asian population, and 27% in African-Americans.

Recall that all cells have sugars (carbohydrates), proteins, or glycoproteins (sugar-protein complexes) that can be recognized by immune cells and these are called antigens. Your blood type is determined by which antigens are or are not on the cell surface of your red blood cells. However, these blood group antigens are not just present on blood cells, but other cells as well, which is why we have to seek out ABO compatible donors for various types of transplants.

Now, recall as far as the SARS-CoV-2 virus that it has a spot on its spike protein called the receptor binding domain (RBD) that attaches to the ACE-2 receptor on the host cells. The RBD binds the ACE-2 receptor beginning the process by which the virus is able to enter the cell, infects the cell, and takes over the cellular machinery that is normally used to make proteins needed by the cell, but once infected, the viral RNA gives this machinery the instructions for how to make the proteins needed for new SARS-CoV-2 progeny that are produced, assembled into a new virus and then expelled from the cell to infect other cells.

What we learn in this article is that the RBD can attach not only to the ACE-2 receptor of many of the body’s cells, but it can also bind to the carbohydrate (sugar) on the red blood cell (and other cells as well) membrane that is the antigenic determinant of blood group. And, all SARS-CoV-2 variants, including delta and omicron (and more strongly for omicron), bind most strongly and preferentially to the sugar that is associated with the A blood group. For example, SARS-CoV-2 is far more likely to infect cells that have the blood group A antigen on their surface than those that have the surface antigen associated with group O. When the virus attaches to the group A blood cell carbohydrate, the virus can enter the blood cell and can then hitch a ride to be distributed anywhere in the body that is supplied by blood, which is almost everywhere. Further, the lung cells of someone with blood group A antigen on their cell surface are far more likely to be infected than those of a person who is type O.

It is interesting that we did not see this enhanced affinity for blood group A cell infection with the original SARS virus or the other coronaviruses.

This does not mean that if you have a blood type other than A you need not worry about getting COVID. This merely gives us more information to consider as to why some people seem to be more likely to get infected than others. SARS-CoV-2 infection is far more complicated than merely your blood type.

I have previously written about the issues surrounding and the evidence-to-date in the public realm as to the origins of SARS-CoV-2. There has been much mystery, intrigue and debate as to the origins of the virus, and while there are relatively minor variations as to specifics, most who have an opinion on this fall into one of two categories –

• those that support a “lab leak,” meaning that laboratory workers, most often alleged to be at the Wuhan Institute of Virology, a lab world-renown for its work on bat coronaviruses, were infected by the virus they were secretly working on and subsequently introduced the virus into the population to begin the pandemic; or
• those that support a zoonotic transmission (animal à human) that most often is alleged to have taken place at the Wuhan Seafood Market that then led to human à human spread and sparked the pandemic.

Personally, having listened intently to both sides of the argument, if I were to make a decision based on the preponderance of the evidence, I would fall into the second group – a zoonotic transmission. You can read my prior blog post for more in-depth analysis, but to briefly sum up the reasons for my belief, they would be:

• Zoonotic transmission, or so called “spill-over” events have been come increasingly more frequent over the recent decades. On the other hand, a lab leak has never sparked a pandemic, let alone, a lesser outbreak.
• I don’t know of any reputable scientist, public health expert or public health agency that does not accept the evidence that zoonotic transmission from palm civets (and/or raccoon dogs) at a “wet” market in China sparked the SARS-CoV outbreak in 2003.
• While I am not convinced that the first case of COVID was in Wuhan, it is clear that the first recognized outbreak was in Wuhan, and cases clearly clustered around the Wuhan Seafood Market from an epidemiological viewpoint.
• The Chinese wet markets were prohibited from having civet cats or raccoon dogs in their markets following the 2003 SARS outbreak, yet we have photographic and DNA evidence that these animals and many others who we know can be infected with SARS-CoV-2 virus were in the market.
• The original wild-type virus developed mutations that led to the identification of two different lineages within 1 – 2 weeks – lineage A and lineage B. This would not be expected if a lab worker had been accidentally infected and transmitted the virus. Rather, this suggests the unsurprising scenario of multiple spill-over events. Keep in mind that the markets source these animals from the southern part of the country (where there are many bat caves) where they are farmed, transported in very close contact with each other and their secretions, and sold to the markets, sometimes illegally and certainly with little, if any, regulatory oversight. Transmission from animal à animal would offer the opportunity for these mutations to develop (especially if that transmission were cross-species) and then the animals arrive in the markets infected, and under the right circumstances (and I describe those circumstances at the markets that would promote transmission in my prior blog post), the animals may transmit the virus to humans.
• While there is much conjecture, there is no evidence made publicly available to support a lab leak (e.g., evidence that the laboratory was using the virus in experiments, evidence of illness of a lab-worker that was subsequently shown to be SARS-CoV-2 (remember, that at the time of this initial outbreak, China was having its influenza season), or evidence of seroconversion of lab-workers prior to the onset of the pandemic (it is customary for labs of this biosecurity level to maintain specimens of blood from each lab worker monthly so that one can go back and check for antibodies to determine if and when someone was infected with a virus they were working with).

Nevertheless, I ended my blog post by stating that given that we knew our government had classified information that was not publicly available and the fact that some of our intelligence agencies had assessed a lab leak to be possible, or even probable, I commented that my own personal assessment was made solely based upon publicly available information and sources. Obviously, knowing that government intelligence agencies had classified information that was not public, meant that my assessment might change if that information ever did become public. Although, even that eventuality was somewhat unlikely given that with the exception of the FBI’s assessment that the origin was a lab leak with moderate confidence, all the other agencies that had determined a lab leak to be more likely than a zoonotic event or alternatively, that a zoonotic spillover event was more likely than a lab leak, all these agencies only offered their assessment with low confidence. If these government agencies had a smoking gun, I would not expect their assessments to be of such low confidence.

Since I wrote that blog piece, the COVID-19 Origin Act of 2023 was passed and called for the U.S. Intelligence Community (IC) to declassify information relating to potential links between the Wuhan Institute of Virology (WIV) and the origin of the COVID-19 pandemic. Note that the law did not call for any of these agencies to review the evidence or potential links between the Wuhan Seafood Market and the COVID-19 pandemic.

Note that the IC is made up of 18 different organizations, but not all, or even most, of these agencies has conducted their own intelligence assessment as to the origin of the pandemic. Members include the:

• Office of the Director of National Intelligence (ODNI) 
• Central Intelligence Agency (CIA)
• Defense Intelligence Agency (DIA)
• National Security Agency (NSA)
• National Geospatial- Intelligence Agency (NGA)
• National Reconnaissance Office (NRO)
• intelligence elements of the five DoD services: the Army, Navy, Marine Corps, Air Force, and Space Force
• Department of Energy’s Office of Intelligence and Counter-Intelligence
• Department of Homeland Security’s Office of Intelligence and Analysis
• U.S. Coast Guard Intelligence
• Federal Bureau of Investigation
• Drug Enforcement Administration’s Office of National Security Intelligence
• Department of State’s Bureau of Intelligence and Research
• Department of the Treasury’s Office of Intelligence and Analysis

The Office of the Director of National Intelligence has now released a redacted report meeting the obligations under the COVID-19 Origin Act prepared by the National Intelligence Officer for Weapons of Mass Destruction and Proliferation.

The report indicates that the first question assessed by agencies was whether the first known human infection was the result of natural exposure to an infected animal or a laboratory-associated incident. The agencies that assessed this question came to different conclusions based upon how they weighed intelligence reporting and scientific reporting, as well as the gaps contained in both. While some agencies:

• have determined they can make no assessment due to insufficient information (this group includes the CIA and an unnamed other agency),
• others have made the determination that a lab leak was more likely than zoonotic spread (this includes the FBI and the Department of Energy, though they make their assessments for different reasons); and
• others have made the determination that a zoonotic spillover event was more likely than a lab leak (this group includes the National Intelligence Council and four IC agencies),

no agency was able to conclude that they could rule out a lab leak or rule out a zoonotic spillover event.

One point of consensus among these agencies is that the SARS-CoV-2 virus was not genetically engineered. The majority of the agencies concluded that the virus was not laboratory-adapted. The agencies were unanimous in concluding that SARS-CoV-2 was not developed as a bioweapon.

The report makes a number of findings:

1. “Some of the research conducted (at WIV) included work with several viruses, including coronaviruses, but no known viruses that could plausibly be a progenitor of SARS-CoV-2.” This was not a secret. WIV and its lead scientist are world-renown for their coronavirus research, many publications in the scientific literature come from this lab, and the researcher is a frequent lecturer at international meetings.
2. WIV was involved in the development of vaccines and therapeutics for coronavirus infections (this is good). “The IC assesses that this work was intended for public health needs and that the coronaviruses known to be used were too distantly related to have led to the creation of SARS-CoV-2.”
3. “We continue to have no indication that the WIV’s pre-pandemic research holdings included SARS-CoV-2 or a close progenitor, nor any direct evidence that a specific research-related incident occurred involving WIV personnel before the pandemic that could have caused the COVID pandemic.”
4. “Information available to the IC indicates that the WIV first possessed SARS-CoV-2 in late December 2019, when WIV researchers isolated and identified the virus from samples from patients diagnosed with pneumonia of unknown causes.”
5. “Before the pandemic, the WIV had been working to improve at least some biosafety conditions and training. We do not know of a specific biosafety incident at the WIV that spurred the pandemic and the WIV’s biosafety training appears routine, rather than an emergency response by China’s leadership.”
6. “An inspection of the WIV’s high-containment laboratories in 2020 – only months after the beginning of the COVID-19 outbreak’s emergence – identified a need to update aging equipment, a need for additional disinfectant equipment, and improvements to ventilation systems.”
7. “Several WIV researchers were ill in Fall 2019 with symptoms; some of their symptoms were consistent with, but not diagnostic of COVID-19. The IC continues to assess that this information neither supports nor refutes either hypothesis of the pandemic’s origins because the researchers’ symptoms could have been caused by a number of diseases and some of those symptoms were not consistent with COVID-19.”
8. “The IC assesses that the WIV maintains blood samples and health records of all laboratory personnel – which are standard procedures in high-containment laboratories.”
9. “We have no indications that any of these researchers were hospitalized because of the symptoms consistent with COVID-19. One researcher may have been hospitalized in this timeframe for treatment of a non-respiratory medical condition.”

To me, all of this is underwhelming. In fact, I now am mystified by how the FBI would assess the likelihood of a lab leak as having moderate confidence. I suspect that this must be related to the approach of law enforcement that when a suspect is not forthcoming or lies, they must be guilty. Certainly, the FBI would have reason to be suspicious, but China had reasons to be covering up a wet market spillover event. This would be the second time a SARS coronavirus would emerge from China. It would be a huge embarrassment, as well as reflect poorly on the government for not controlling the wildlife trade at the markets.

Frankly, the fact that any of the agencies leaned towards the lab leak theory appears to be based on the fact that none, or at best few, of them evaluated the evidence for a zoonotic spillover event. I know that we have some of the best intelligence-gathering capabilities in the world, but the approach to this investigation has really shaken my confidence in these intelligence assessments. Frankly, we likely need an intelligence agency that has the expertise to investigate outbreaks. We already have this expertise in USAMRIID and the CDC. It seems to me that an intelligence agency with these kinds of experts in infectious diseases, epidemiology, evolutionary biologists and disease outbreak investigation experts might be better able to evaluate the merits of lab leak vs. zoonotic spillover event, rather than merely focusing on the feasibility of a lab leak.

We have only eradicated one virus from the world – smallpox. We were so close to eradicating poliovirus, but like the old saying: ”close only counts in horseshoes and hand grenades.”

Poliovirus causes asymptomatic infection in most people (~70 – 75%). There is wide-ranging potential illness in the 25 – 30% who become symptomatic. The most feared manifestation of poliovirus infection is poliomyelitis, first described in 1789 in England.

Poliovirus caused increasingly severe epidemics in the northern hemisphere each summer and fall in the first half of the 20^th century. If you were a parent with small children in the early 1950’s, you no doubt remember the fear of poliomyelitis in children, the uncertainty as to how children were being infected, the pool closures for fear of contracting poliomyelitis, the public service announcements at the beginning of movie shows at theatres and the images of children in iron lungs as well as the recovered children and adults in leg braces to assist them in walking.

By 1952, there were more than 21,000 cases of poliomyelitis (sometimes called paralytic polio) reported in the U.S.

Parents expressed great relief when effective vaccines were introduced (inactivated poliovirus vaccine (IPV) in 1955 and oral poliovirus vaccine (OPV) in 1961). There were long lines wrapping around buildings where vaccines were being administered for those awaiting the opportunity to get vaccinated.

The vaccines worked. The rate of new poliovirus cases precipitously declined, and poliovirus infections from the wild-type virus were eliminated in the U.S. in 1979.

Poliovirus

Poliovirus is a picornavirus that belongs to the group of viruses referred to as enteroviruses. It is an RNA virus.

There are three serotypes (a serotype refers to an antigenically distinct form of the virus – think of this in a similar way that you would think about strains, although technically, they are not the same) of the poliovirus (type 1, type 2 and type 3). My reference to the serotypes being antigenically distinct means that immunity to one type does not confer significant cross-protection to the other types. (Recall that antigens are proteins on the surface of bacteria and viruses that the body recognizes as not being itself. In response, the body produces antibodies that bind to the antigens, hopefully preventing the virus from being able to enter a cell (we call these neutralizing antibodies), but even if neutralizing, the antibody can “tag” the virus so that certain immune cells (cytotoxic T-cells) recognize it as something to ingest and destroy with their intracellular enzymes and chemicals.)

Poliovirus enters the body through the mouth and begins to replicate in the mouth and throat, but continues its infection and replication in the gut. The virus is then passed in the infected person’s stool for several weeks (even if the infected person is without symptoms) and can infect others when the other person’s hand comes into contact with virus from the infected person’s stool and they in turn ingest it. Symptomatic polio disease (other than poliomyelitis) generally appears within 3 – 6 days of infection. (Paralytic poliomyelitis generally doesn’t appear until 7 – 21 days following infection.)

While the poliovirus is infecting cells lining the gut, it can get into the lymph tissue and nodes that are in close proximity, and in turn, enter into the blood stream, the route by which poliovirus can infect the brain and spinal cord, destroying the major cells responsible for movements of muscles. The resulting paralysis is often permanent, especially if there has not been significant improvement over the course of the first year following infection.

The majority of those who develop symptomatic infection have symptoms such as low-grade fever and sore throat. They typically recover in days to a week.

Anywhere from 1 – 5% of children infected with poliovirus will develop aseptic meningitis (this can manifest as headache, stiff neck, fever, vomiting and intense discomfort of the eyes when in bright light). However, these children do not experience paralysis (it may appear initially that they have muscle weakness, but generally that is because of stiffness and aching in the extremities and therefore they avoid movements or putting weight on their legs, which generally resolves within days).

The frequency of paralytic polio (poliomyelitis – literally, inflammation of the spinal cord due to poliovirus) varies with each different serotype, but generally is seen in less than 1% of cases.

The case fatality rate (CFR = number of deaths divided by the number of patients identified with the disease) for poliomyelitis is 2 – 5% in children. For adolescents and adults who develop poliomyelitis, the CFR can be as high as 15 – 30%. While most paralytic cases involve the legs, a small percentage of people develop what we call bulbar polio that unfortunately causes weakness of the facial muscles, the muscles involved in talking and swallowing, and potentially even the muscles associated with breathing (thus the pictures of patients in iron lungs in hospitals). The CFR for these patients can range from 25 – 75%.

Few people have an appreciation for the fact that infection with certain viruses earlier in their lives may cause problems later in life. For those who are somewhat aware, they likely will cite infection with chickenpox that can cause shingles decades later in life as one of the most common such examples. However, there are many examples, including viruses that can cause certain cancers (we refer to these as oncogenic viruses), and the most recent discovery that infection with the Epstein-Barr virus in children or young adults can cause multiple sclerosis later in life. I have written many blog posts exploring the long-term health consequences we are seeing in patients who had seemingly recovered from COVID-19.

With poliovirus infection, 25 – 40% of persons who developed poliomyelitis in childhood experience new onset of muscle pain and a worsening of their weakness or new weakness or paralysis 15 – 40 years after their initial infection, a condition referred to as post-polio syndrome.

We nearly were able to add poliovirus as the second virus to be eradicated, however, Pakistan and Afghanistan did not successfully vaccinate their populations sufficiently to eliminate the wild-type virus from their countries, and, as a consequence, polio is endemic in those two countries. Of concern, we have started to see wild-type virus cases pop up in certain African countries.

When outbreaks of polio occur, we vaccinate those around them. Ideally, we would use the inactivated vaccine (IPV) because that vaccine does not contain viable virus that can infect people. However, IPV is administered by injection, and this is much more difficult to mobilize to a large group of people in remote and underdeveloped areas of the world. For that reason, the oral vaccine (OPV) is used, however, this vaccine contains attenuated (weakened, but not inactivated) virus. While it protects the person being immunized, the attenuated virus can “revert” in that person’s gut so that when the vaccinated person passes the virus in their stool, it now may infect people who come into contact with that person and who are not protected. The most recent case of poliomyelitis in a resident of New York state was due to a reversion of a vaccine strain of virus – most likely, because of no recent international travel by this person, a result of another person from one of those countries that still uses OPV (we stopped using OPV in the U.S. in the 70’s) who was passing the vaccine-derived virus in their stool and traveled to NY, where the American, who was unvaccinated, came into contact with the virus.

Thus, there is concern with the risk for wild-type virus infection among travelers to countries where the wild-type virus remains endemic, but also to countries that are immunizing their populations only with OPV and have circulating vaccine-derived poliovirus.

Thus, if you plan on international travel with children in the future, it is essential that you get them fully vaccinated if they have not previously been. The polio vaccination schedule for children is 4 doses in total of vaccine given: (1) at 2 months of age; (2) at 4 months of age; (3) sometime between the ages of 6 and 18 months; and (4) on or after the 4^th birthday with at least a 6-month interval since the third dose.

The CDC has issued a Level 2 travel advisory that calls for enhanced precautions if you are travelling to any of the following countries:

1. Afghanistan
2. Algeria
3. Benin
4. Botswana
5. Burundi
6. Cameroon
7. Canada
8. Central African Republic
9. Chad
10. Cote d’Ivoire
11. Democratic Republic of the Congo
12. Djibouti
13. Egypt (healthcare facilities, refugee camps and humanitarian aid settings only)
14. Ghana
15. Indonesia
16. Israel
17. Madagascar
18. Malawi
19. Mali
20. Mozambique
21. Niger
22. Nigeria
23. Pakistan
24. Republic of the Congo
25. Somalia
26. Sudan
27. Togo
28. United Kingdom
29. Yemen
30. Zambia

Before traveling to any of these countries, adults who have completed the full routine vaccine series should receive a single, lifetime booster dose of polio vaccine.

A new study (Trends in Laboratory-Confirmed SARS-CoV-2 Reinfections and Associated Hospitalizations and Deaths Among Adults Aged ≥18 Years — 18 U.S. Jurisdictions, September 2021–December 2022 | MMWR (cdc.gov)) examines the epidemiological trends of SARS-CoV-2 reinfections and the association with severe outcomes.

The investigators report that during the time period of September 2021 (Delta) to December 2022 (Omicron), the percentages of reinfections among cases, hospitalizations and deaths all increased significantly as reported by 18 jurisdictions in the U.S. Increases were most pronounced among young adults ages 18 – 49 years compared with older adults. On average, 12.7% of all infections during this time period were reinfections. The increase in reinfections is likely related to the increasing transmissibility and immune evasion of Omicron variants.

 As a percentage of all infections, reinfections increased substantially from the Delta (2.7%) to the Omicron BQ.1/BQ.1.1 (28.8%) periods. During the same periods, increases in the percentages of reinfections among COVID-19–associated hospitalizations (from 1.9% [Delta] to 17.0% [Omicron BQ.1/BQ.1.1]) and deaths (from 1.2% [Delta] to 12.3% [Omicron BQ.1/BQ.1.1]) were also substantial.

Percentages of all COVID-19 cases, hospitalizations, and deaths that were reinfections were consistently higher across variant periods among adults aged 18–49 years compared with those among adults aged ≥50 years.

Among persons reinfected in September 2021, 90.5% had been previously infected during the period when the ancestral strain was predominant (2020), and 9.5% had been previously infected during the Alpha variant period (early 2021). 

The median interval between infections ranged from 269 to 411 days, with a steep decline at the start of the BA.4/BA.5 period, when >50% of reinfections occurred among persons previously infected during the Alpha variant period or later. 

Higher percentages of reinfections among COVID-19 cases and associated hospitalizations and deaths were observed among younger adults compared with older adults, particularly in late 2022. The higher percentages in younger age groups might be attributable to multiple factors, including higher cumulative incidence of first infections, later eligibility for vaccination, lower vaccination coverage, increased exposure risk, and a possible survival bias because of less severe initial infections. 

I fear that many people that have been previously infected are under the impression that they will have durable immunity resulting from the infection. There is mounting evidence and every reason to believe that infection-based immunity wanes similar to vaccination-induced immunity. I also fear that people previously infected are under the impression that subsequent reinfections will necessarily be milder and therefore not consider obtaining early treatment with antivirals for those with above average risk.

Further, it has become clear that the risk for Long COVID or PASC (post-acute sequelae of COVID-19 infection) increases with each reinfection.

For the First Time Ever, there will be an RSV (Respiratory Syncytial Virus) Vaccine Available this Fall for Older Americans

Respiratory Syncytial (pronounced “sin-sish-uhl”) Virus (RSV) is a common respiratory virus that for most people is little more than a bad cold resolving on its own within a week or two, but for infants (and some older children) and the elderly, it can be quite serious and even deadly. We generally see RSV activity from October to May each year in the U.S.

We divide how people present to our offices or emergency rooms with respiratory infections as upper respiratory tract infections (URIs) (those whose signs and symptoms are predominantly involving the throat and above – runny nose, nasal congestion, sore throat, and/or non-productive cough) and lower respiratory tract infections (those with signs and symptoms relating to the lungs – chest tightness, shortness of breath, wheezing, cough with sputum production, abnormal breath sounds when we listen with a stethoscope, and/or abnormal changes on the chest x-ray).

RSV is the major cause of lower respiratory tract infections in children. RSV is the most common cause of bronchiolitis (inflammation of the small airways) and pneumonia in children in their first year of life, and a common cause for hospitalization of young children during the cold and flu season. RSV is one of the respiratory infections that can cause croup (a protracted, barking-like cough and sometimes accompanied by a high-pitched creaking or whistling sound when the child breaths in).

Almost everyone will be infected with RSV within the first few years of their life. However, people do not develop a robust immune response and memory to RSV, so reinfections are common. (That is one of the reasons it has been so difficult to develop a vaccine against RSV.)

People generally develop symptoms within 4 – 6 days after being infected and symptoms generally include a runny nose, coughing, sneezing, wheezing and fever. Infants may stop eating or nursing due to the difficulty of doing so while working so hard to breathe.

RSV was first isolated and identified from chimpanzees with colds in 1956. Shortly thereafter, the same virus was identified in young children with respiratory illnesses. RSV is an RNA virus, as are influenza and SARS-CoV-2. By now, everyone is aware that the spike protein of SARS-CoV-2 is important in binding to the ACE-2 receptor on cells to enable the virus to infect the cell and is an important immune target for developing neutralizing antibodies (neutralizing antibodies bind the protein in such a way as to inhibit the virus’ ability to attach to the cell receptor and infect the cell). RSV is a completely different virus than SARS-CoV-2 and has a different structure and a different cell receptor it binds to.

Rather than the S (spike) protein of SARS-CoV-2, RSV has an F (fusion) protein that is important for fusing together the membranes of the virus and the cell to allow the virus to enter and take over the cell’s machinery to make new viruses directed by its RNA genetic code. During the process of infecting a cell, the F protein morphs from its pre-fusion structure, which has a number of sites that provide the body’s immune system with neutralizing antibodies to a post-fusion form, which provides the body with fewer and weaker neutralizing antibody targets.

There are two strains of RSV – A and B – but there are many subtypes of each.

On May 3, 2023, GSK’s RSV vaccine (Arexvy) using the prefusion form of the F protein was approved as a single dose vaccine for those 60 years of age and older for the prevention of lower respiratory tract disease from RSV infection. This vaccine was studied through two full RSV seasons. Lower respiratory tract disease was distinguished from upper respiratory tract disease by at least 1 lower respiratory sign or if no respiratory signs, at least 3 lower respiratory symptoms, lasting for at least 24 hours. (A symptom is something that a patient feels and reports, but generally we cannot objectively measure – e.g., sore throat, stuffy nose or shortness of breath, whereas a sign is something that we can observe or measure and the patient may not even be aware of– e.g., rapid breathing or low oxygen levels).

The vaccine effectiveness (VE) for Arexvy was 82.6% during the first RSV season following vaccination, 80.9% when measured mid-way through the second season, and 56.1% by the end of the second season. However, the VE against severe lower respiratory tract disease was better (as expected) and more durable (VE 94.1%, 86.8% and 64.2%, respectively). Interestingly, giving a second dose of vaccine in advance of the second season did not improve the VE.

The studies also showed that it was safe and effective to administer flu vaccine at the same time as the RSV vaccine (this is important for patient convenience so that they can make fewer trips given this population may have more mobility issues and difficulty driving or arranging for transportation).

On 5/31/2023, the FDA gave approval for Pfizer’s Abrysvo vaccine for persons age 60 and over for the prevention of lower respiratory tract infections resulting from RSV. The vaccine uses the F protein of the RSV in its pre-fusion form.

The VE was assessed against symptoms of lower respiratory tract disease symptoms over two RSV seasons (the RSV season of one year, followed by the mid-point of the next season one year later). The VE in preventing 3 or more lower respiratory tract disease (RSV-LRTD > 3 symptoms) was 88.9% for the first year and 78.6% at the mid-point of the second RSV season.

The VE in preventing 2 or more symptoms of lower respiratory tract disease (RSV-LRTD > 2 symptoms) was 65.1% for the first RSV season and 48.9% at the middle of the RSV season in the second year.

Studies of Pfizer’s RSV vaccine did not reveal any safety concerns and demonstrated that it could be safely administered together with the influenza vaccine, without any impairment to its protection against RSV.

This is wonderful that we now have two vaccines available for older adults to protect against a common respiratory infection that can cause respiratory illness serious enough to hospitalize 60,000 – 160,000 seniors each year, with 6,000 – 10,000 deaths expected each year.

However, there are still some challenges:

• It is not always possible to predict the onset of RSV season, and we have recently experienced some earlier upticks in disease than expected.
• None of the studies evaluated the safety and efficacy of administering RSV vaccine, influenza vaccine and the COVID booster shot that many older adults are going to want to receive this fall.
• Both new vaccines are approved for adults ages 60 and over, but what about those under age 60 who are immunocompromised?

If you are age 60 or older and are on the fence about whether to get this vaccine, I would use any of the following factors to push you over the fence to the side of getting the vaccine:

• You will be around young children during the cold and flu seasons (e.g., a grandparent of young grandchildren (especially 2 and under), working in a daycare setting, volunteering as a Sunday school teacher for young children, etc.)
• You have underlying lung problems (asthma, bronchitis, emphysema, etc.)
• You have significant underlying heart disease
• You reside in a skilled nursing facility or long-term care facility
• You are immunocompromised

If you have other underlying chronic medical conditions, be sure to discuss whether you would likely benefit from RSV vaccination with your doctor or other regular care provider.