Category: Epidemiology

Two weeks ago, the new COVID booster vaccines were released and the internet is full of articles titled “Should you get a COVID booster?“. This is the wrong question – the real question is “When should you get a COVID booster?”. We so want the COVID pandemic to be over and gone. Americans are returning to theaters and restaurants, houses of worship are full again, sporting events are sold out, and mask-wearers are a tiny minority at the grocery stores. But COVID is not going away.

For the past 3 years, there have been two peaks of case numbers every year – a large peak in January and a smaller peak in the summer. Data from the CDC this week indicates that the current 2023 summer peak is cresting and cases should begin to fall over the next few weeks (reported case numbers are unreliable but COVID hospitalizations, COVID deaths, and the percent of ER visits due to COVID are accurate measures). If history repeats itself, then we should have a break in cases for the next couple of months until they begin to rise again in the winter.

COVID is a moderately lethal infection – less lethal than Ebola but more lethal than influenza. Immunity is very effective in protecting you from dying of COVID but less effective from protecting you from catching a non-fatal COVID infection. There are two ways to get immunity – either by having a previous COVID infection or by getting a COVID vaccine (or both). On the whole, immunity from past infection is probably more effective than immunity from a vaccine. However, to get immunity from a past infection, you have to first survive the infection. There are a number of advantages to getting immunity from a vaccination compared to getting immunity from an actual COVID infection:

So far, 1,144,539 Americans have died from COVID and most of these were people who had no immunity to the virus and died from their first infection. To understand how our immune system fights COVID, let’s first take a look at the basics of the immune response to viruses.

How the immune system works

Viruses cannot reproduce on their own – they have to get inside of our cells and then hijack those cells’ RNA to produce new viruses. Our defense against viruses takes two forms: the innate immune system and the adaptive immune system. Innate immunity uses parts of the immune system that we are born with to fight any new infection. The innate immune system consists of interferons, natural killer lymphocytes, and macrophages. When a cell gets infected with a virus, that cell releases interferons that then signal natural killer cells to kill any other infected cell before it can produce more viruses. In addition to stopping the infection by killing infected cells, the innate immune system has macrophages that can eat and kill extracellular viruses before those viruses can infect other cells in the body. The innate immune system works whether or not a person has been previously infected with the same virus or has received a vaccine against that virus. Think of the innate immune system working on instinct. The adaptive immune system, on the other hand, can be thought of as working by learning. Of the two, the adaptive immune system is the more powerful.

The adaptive immune system learns from previous infection or vaccination so that when a person is exposed to a future infection, the adaptive immune system can be immediately activated against that virus. The adaptive immune system consists of T-lymphocytes, B-lymphocytes, and antibodies. When a person is first infected with a virus, T-lymphocytes become activated and then in turn activate B-lymphocytes to produce antibodies that are specifically directed against that particular virus. These antibodies are our immune system’s most important weapon against viruses and can defeat viral infections in four ways. First, antibodies can bind to the virus so that the virus cannot get into cells and thus prevent the virus from infecting cells. Second, when antibodies bind to a virus, it signals macrophages to eat and kill that virus. Third, when antibodies bind to an infected cell, they mark that cell for natural killer lymphocytes to kill that infected cell, thus preventing further viral replication. Fourth, when antibodies bind to infected cells, they activate the complement system to punch holes in that cell, thus killing it and preventing further viral replication. Antibodies last for about a month in the bloodstream and after an infection is resolved, the adaptive immune system cuts way back on new antibody production.

The innate immune system works immediately after an infection but it takes the adaptive immune system 1 – 3 weeks to ramp up antibody production after a new infection. However, the second time a person is infected with the same virus, that adaptive immune system can ramp up antibody production much faster, in a matter of days rather than weeks. This is because of memory T-lymphocytes and memory B-lymphocytes that have learned how to make antibodies against that particular virus. These memory cells cause antibodies to be produced much faster than during the first, initial infection with a virus.

Antibodies and COVID

Many people who are now getting infected with COVID are on their second or third infection. For most people, the second infection is not as severe as the first and the third infection is not as severe as the second. This is because the memory T-lymphocytes and memory B-lymphocytes allow the immune system to respond faster and more effectively against repeat infections. Multiple doses of vaccines do the same thing – with each vaccine dose, your body makes new antibodies against COVID variants covered by that vaccine booster and also trains your memory lymphocytes to ramp-up antibody production quickly if you are exposed to the virus in the future.

Because antibodies only have a lifespan of about a month, antibody levels fall after either an infection or a vaccination as the B-lymphocytes start to slow down antibody production. As a result, after vaccination, COVID antibody levels begin to fall after about 3 months. So, you are best protected against a future infection in the first 3 months after a COVID vaccine as well as in the first 3 months after a COVID infection. But what most people do not realize is that it is not just the antibody levels in the blood that protect against COVID infection but it is also the training of the memory T-lymphocytes and memory B-lymphocytes that protect against infection Those memory cells last many years and can sometimes last for a lifetime. We have blood tests that can measure antibody levels but we do not have blood tests that measure memory lymphocyte levels and consequently, this important effect of vaccination is often overlooked.

When you get a COVID mRNA vaccine, you produce antibodies against one small part of the COVID virus. On the other hand, when you get a COVID infection, you produce antibodies against many different parts of the COVID virus. For that reason, a COVID infection will stimulate stronger immunity against another future infection than vaccination does. But because the memory T-lymphocytes and memory B-lymphocytes learn from each exposure to a virus or to a vaccination, the more you stimulate those memory cells, the better they become at fighting infection. Also, because antibody levels eventually fall after a COVID infection, those antibody levels can be replenished if a person gets vaccinated several months after that infection. For these reasons, a COVID vaccination gives you good immunity, a COVID infection gives you better immunity, and a COVID infection plus a vaccination gives you the best immunity.

So, when should you get a COVID vaccine?

Early in the pandemic, the answer to this question was easy – everyone should get a COVID vaccine as soon as possible. However, now that most Americans have at least some degree of immunity from either previous vaccination, previous COVID infection, or both, the answer to the question is a bit more complicated. In order to get the maximum benefit from vaccination, the timing has to be individualized. And the key to individualization is the fact that antibody levels persist for about 3 months after infection or vaccination before those levels begin to drop off. So, here are my recommendations:

• No previous vaccination or infection. These are people who are most likely to become severely ill or die if they get a COVID infection. They should get vaccinated immediately. Even if COVID case numbers in their community are low, it is not worth gambling with one’s life that they won’t be exposed to an asymptomatic person at the grocery store, at church, or at work.
• Received an older COVID vaccine within the past 3 months. These people should wait until at least 3 months after their last vaccination. Their antibody levels are already high and it is better to wait until their antibody levels begin to fall before re-stimulating their adaptive immune system. However, given the anticipated January surge in COVID numbers, they should not wait long after that 3-month period.
• Had a COVID infection in the past 3 months. These people should similarly wait until at least 3 months after their COVID infection. However, they should also get vaccinated before the anticipated winter surge in cases.
• Previous vaccination more than 3 months ago and no previous infection. These people should time their vaccine to when they are most likely to be exposed to COVID. For the last 3 years, the winter peak of COVID cases has been in the first week of January. Assuming this year is similar, then get a new COVID vaccine now and by mid-November at the latest.
• Previous vaccination more than 3 months ago and had a previous infection. Congratulations – these people already have the strongest immunity. But their immunity will be even stronger with a new COVID vaccine now or by mid-November at the latest.
• Moderately or severely immunocompromised. Here is where things get a bit complicated. These people need more vaccine doses in order to be protected. If they have never been vaccinated, they should receive 3 doses of either the new Pfizer or the new Moderna COVID vaccine. If they have previously received 1 dose of either Pfizer or Moderna, then they should receive 2 doses of either of the new COVID vaccines. And if they have received 2 or more Pfizer or Moderna vaccinations in the past, they should receive 1 dose of either of the new COVID vaccines. If you are uncertain, it is better to err on the side of too many rather than too few doses for immunocompromised people.
• Planning travel or large family get togethers over Thanksgiving or Christmas. Get a COVID vaccine now (or by the end of October at the latest) in order to ensure that you have protective antibody levels over the holidays. First, because it will protect you from getting infected while traveling and second, because you don’t want to get an infection just before your travel date and have to cancel your trip.

There are three COVID vaccines currently on the market. The Novovax protein subunit vaccine is based on the original strain of COVID and is only approved for primary vaccination in people who have never received any COVID vaccines; it is not available as a booster. Anyone who received the Novovax (or the no-longer available J&J vaccine) still needs to get one of the new mRNA vaccines since neither Novovax nor J&J covers the newly circulating COVID variant. The new Moderna and Pfizer mRNA vaccines are available for anyone for either primary vaccination or as a booster. The new Pfizer and Moderna vaccines are interchangeable so if you have previously received a Moderna vaccine, you can get either a Moderna or Pfizer booster and vice-versa.

The bottom line is that everyone should get a new COVID vaccination

Your body’s immune system is like your muscles – the more you train it the stronger it becomes. Vaccinations both keep your antibody levels high and train your immune system to make new antibodies rapidly and in large quantities. There are really no good reasons to not get vaccinated. Everyone should get vaccinated in the next 6 weeks to optimally protect themselves during the upcoming holidays and the anticipated upcoming winter surge in COVID numbers. The Moderna vaccine or the Pfizer vaccine – either one is fine, no matter what brand of vaccine you have received in the past.

And, oh by the way… get your other protective vaccinations, too. I got my influenza and pneumococcal vaccines together on September 1st and my RSV and new COVID vaccines together on September 18th. This was my 6th dose of a COVID vaccine since December 15, 2020. My immune system will be ready for whatever gets thrown at it this winter.

October 2, 2023

Since the beginning of the COVID pandemic, there have been two surges in COVID cases and deaths every year, one in the winter and one in the summer. Because of this, it was predicted that the U.S. would seen a new surge this summer and epidemiology data indicates that it is now starting. The graph below shows the COVID death winter surges in red and summer surges in black.

However, the peaks in COVID deaths lag about 3 weeks behind the peaks in cases. The typical timeline for a person who dies of COVID is to develop initial symptoms one week before hospitalization and then have a 2-week hospitalization before death. COVID hospitalizations in the United States are now beginning to rise. In the graph below, the weekly new hospital admission number has been increasing for the past two weeks and currently number weekly hospitalizations are 8,035, up 12% from the week before.

An even earlier indicator of COVID surges is the COVID test percent positivity. The percentage of COVID tests that are positive starts to rise before the number of hospitalizations and even before the total number of cases. The graph below shows The test percent positivity in yellow and the deaths in blue.

In the graph above, we can see that the test percent positivity began to increase in early July 2023, suggesting that a COVID surge is eminent. But the COVID percent positivity data can be inaccurate because it is dependent on COVID tests that are reported to health departments. Since many people do home tests that are not reported to health departments, many positive (and negative) tests will be missed.

Another harbinger of COVID surges is the percentage of emergency department visits that are due to COVID infections. Because initial symptoms precede hospitalizations by a week or two, people infected with COVID will often present to the ER before getting sick enough to require admission to the hospital. The graph below shows that surges in the percentage of ED visits that are due to COVID (yellow) precede surges in COVID deaths (blue) by several weeks. Once again, we see that the percentage of ED visits due to COVID began to rise in early July.

Another predictor of COVID surges is COVID sewage wastewater sampling. People infected with COVID will shed virus into household wastewater very soon after becoming infected – often before developing symptoms or getting tested. By testing municipal wastewater for COVID viruses, we can detect surges in COVID early. The graph below shows changes in virus levels from more than 1,200 wastewater testing sites throughout the U.S. The red shade indicates the percentage of samples that show a greater than 100% increase in virus levels and is now the highest it has been since January 2023.

So, what should physicians be doing now?

In the past 3 years, the summer COVID surges have been smaller than the winter surges so if history is any indicator, then the current COVID surge should not overwhelm our hospitals. However, medically vulnerable people are at risk of severe infection or death, including those who are older, obese, or have chronic medical conditions. In addition, with schools opening this month, there is the potential for rapid spread of COVID among children. Here are some practical steps physicians should be taking now:

• Step up vaccinations. Fewer than 50% of Americans have received an updated bivalent COVID vaccine. Physicians should especially target at-risk individuals for vaccination counseling. This includes pregnant women, the obese, diabetics, the immunocompromised, and those over age 65. The CDC recommends that all people older than 6 months get 1 dose of a bivalent vaccine and those over age 65 or immunocompromised get a second dose of a bivalent vaccine.  New monovalent vaccines directed against the XBB.1.5 variant are expected in October but patients should be told to not wait until then to get vaccinated with a current bivalent vaccine.
• Have a low threshold for testing. Your patient’s sinusitis or common cold is now more likely to be a COVID infection than it was a couple of months ago. Encourage any patient with possible COVID symptoms to be tested. Even if a person’s COVID infection is too mild to warrant treatment, all infected persons need to be in isolation to prevent transmission to more vulnerable people.
• Be familiar with isolation guidelines. The CDC recommends that all people who test positive be isolated for 5 days and after at least 24 hours have passed since a fever. After the isolation period, infected persons should wear a face mask for an additional 5 days when in public. People with more severe infection should remain in isolation for 10 days, rather than 5 days.
• Review current treatment recommendations. The COVID treatment guidelines by the National Institutes of Health are regularly updated. For outpatients, be familiar with the indications for Paxlovid. For inpatients, be familiar with the indications for remdesivir, dexamethasone, heparin, baricitinib, and tocilizumab.
• Advise patients about COVID trends in your community. Our patients are constantly subjected to conflicting and often misleading information about COVID from the media and from on-line sources. Physicians are often the most trusted source of reliable information for patients. Educate patients when they come into the office and harness group messaging through the electronic medical record system.
• Normalize masking in high risk settings. High population density indoor settings pose the greatest risk of COVID transmission. This includes churches, airports, aircraft, trains, buses, and stores during busy times of the day. Encourage patients to carry masks with them and then wear them if crowded indoor settings cannot be avoided.

COVID will be with us for the long-term. Inevitably, there will be periodic surges in cases and it appear that one of these surges is underway this month.

August 8, 2023

After two and a half years of the COVID pandemic, influenza has become an after thought for many Americans. But influenza can still kill vulnerable people and even in otherwise healthy individuals, it can cause unpleasant illness, require time off of work, and cause school absences. One of the best predictors of the next U.S. influenza season is the current Australia winter influenza season that occurs during the U.S. summer.

When will the U.S. influenza season start?

The Australian Government Department of Health and Aged Care publishes an influenza epidemiology report every 2 weeks. The most recent report is from July 23, 2023.

The current influenza data is depicted in the red line in the graph above. Last year’s influenza data is in the taller orange line and the 5-year average is in the black line. In this graph, week 1 corresponds to the week of January 1, 2023. Cases of influenza began to be reported early in Australia this year and most closely matched the 2019 influenza season. Cases started to increase in number in week 8 (late February), had an initial plateau from weeks 13 – 17 (late March to late April), then rose to a peak in week 26 (last week of June).

The Centers for Disease Control publishes a weekly influenza report on the FluView website. The United States influenza season is about 6 months later than the Australian influenza season, owing to the seasonal difference between the northern and southern hemispheres. The graph below shows U.S. influenza data for the last several years with the 2022-2023 data in red. Similar to last year in Australia, influenza was seen earlier and peaked earlier in the U.S. last year.

Based on the current year data from Australia, cases of influenza would be expected to begin to rise in late August or early September in the U.S. and then peak in approximately late December or early January. This would be a much earlier influenza season than is typical in the U.S. and would resemble last year’s influenza season.

What influenza subtypes are likely?

Influenza A and influenza B are the most common varieties of influenza in humans. Each of these can be further divided into common subtypes. The most common subtypes of influenza A are H1N1 and H3N2. The most common subtypes of influenza B are the Victoria lineage and the Yamagata lineage. Each of these subtypes can be further divided into clades and each clade can be divided into subclades. Because influenza can and does mutate regularly, the dominant subclades causing human infection change from year to year. Additionally, the relative percentage of influenza cases caused by influenza A & B varies each year and the relative percentage of each influenza subtype also varies each year. The graph below shows the strains of influenza in the U.S. last year. Most cases were influenza A and most of the influenza A was H3N2 (71%, red bars); H1N1 was much less frequent (29%, orange bars). Influenza B cases were relatively uncommon and mostly seen late in the season (green bars). Notably, all of the influenza B cases were caused by the Victoria lineage (100%) and none were caused by the Yamagata lineage.

This year in Australia, influenza A (63%) was more common than influenza B (35%). The vast majority of influenza A was caused by the H3N2 subtype (82%; dark green bars) as opposed to the H1N1 subtype (18%; purple bars). For influenza B, 100% were caused by the Victoria lineage and none were caused by the Yamagata lineage.

Influenza A H3N2 clades and subclades.  The two clades of H3N2 which are currently in circulation are clade 1 (limited to China) and clade 2 (the dominant clade in the U.S.). In the figure below, clade 1 is shown in purple and clade 2 is shown in green. Each clade is divided into subclades based on mutations in the influenza hemagglutinin gene. The hemagglutinin protein is located on the surface of influenza and helps the virus bind to human cells. Hemagglutinin is also the target for influenza vaccines.

Influenza A H1N1 clades and subclades.  The two clades of H1N1 which are currently in circulation are 5a.1 and 5a.2. The H1N1 5a.1 influenza clade mostly made up of the subclade A/Hawaii/70/2019. This subclade is decreasing in frequency and is rarely seen in the United States.

Most H1N1 influenza in the United States is from clade 5a.2. H1N1 5a.2 subclades A/Victoria/4897/2022 and A/Wisconsin/67/2022 are dominant in the U.S. whereas H1N1 5a.2 subclade A/Sydney/5/2021is dominant in Australia.

Influenza B subtypes. Of the two influenza B lineages, only the Victoria lineage is currently circulating on Earth and the Yamagata lineage has not been detected in the U.S. or Australia in the past year. As with influenza A, mutations in the hemagglutinin gene creates clade diversity in influenza B. Currently, the 1A.3a.2 strain accounts for 99% of influenza B worldwide.

The 2023 – 2024 influenza vaccine

Every year, the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) meets in the spring to project which influenza clades and subclades are likely to circulate during the next influenza season and then selects representative virus strains to use to manufacture the next seasonal influenza vaccines. Because the committee meets in early March, data from the Australia influenza season are not yet available when the U.S. selects influenza strains for vaccines. This year, the strains selected for the quadrivalent vaccines are similar to last year’s vaccine with the exception of the influenza A H1N1 strains; the Victoria/4897/2022 strain replaces last year’s Victoria/2570/2019 and the Wisconsin/67/2022 strain replaces last year’s Wisconsin/588/2019 strain:

The 2023-2024 trivalent influenza vaccines will be similar to the 2023 – 2024 quadrivalent cell-based and egg-based vaccines except that they will not include the Phuket/3073/2013 influenza B strain against the Yamagata lineage. Because there have been no Yamagata lineage influenza B infections in the U.S. last year or in Australia this year, it is likely that the trivalent vaccine will be equally effective as the quadrivalent vaccine this year since coverage for the influenza B Yamagata lineage is unnecessary.

Recommendations

When to get vaccinated. Because the Australia influenza season started early, it is likely that the U.S. influenza season will also start early. Physicians should start vaccinating patients in mid-August and aim to get all patients vaccinated by late October.

Quadrivalent versus trivalent. Because there has not been any recent influenza B Yamagata lineage virus circulating recently, the trivalent vaccine should be just as effective as the quadrivalent vaccine. Therefore, patients can get either vaccine and they can be used interchangeably.

When will hospitalizations peak? This year in Australia, hospitalizations peaked between weeks 19 and 28. This would correspond with early November through early January in the United States. This is normally a busy time for elective inpatient surgeries (such as knee and hip replacements) so hospitals should be prepared accordingly.

The holiday travel effect. Because influenza may be peaking during the U.S. Thanksgiving and Christmas holidays, there is the potential that travel for these holidays could fuel a surge in influenza cases.

Universal flu vaccines in the future?

Because the influenza hemagglutinin gene mutates so readily, the antigen targets on the hemagglutinin surface protein change. This requires new vaccines to be made to generate antibodies against these altered hemagglutinin antigens. The mRNA vaccines that were so successful against COVID offer the hope that mRNA technology could be applied to other anti-viral vaccines, including influenza. A study published November 2022 in the journal Science found that an mRNA vaccine that covered 20 strains of influenza was effective in mice and ferrets. However, recent human trials with mRNA influenza vaccines by Sanofi and Moderna were unsuccessful, mainly due to inadequate immune protection against influenza B strains. Another influenza mRNA vaccine created by Pfizer is currently undergoing phase III clinical trials.

In all likelihood, it will be several years before a universal influenza vaccine is commercially available. Until then, we will have to continue our current process of tracking the dominant circulating influenza clades and subclades in order to produce annual influenza vaccines. Based in Australia’s current influenza season, I recommend getting this year’s flu shots as soon as they are available.

August 2, 2023

This week represented a landmark event in the COVID-19 pandemic: the major epidemiological metrics together were at their lowest points in the U.S. since the pandemic began three years ago. The weekly total cases fell to 77,294, weekly deaths were 1,109, death rate was 0.33 per 100,000, and weekly new hospital admissions were down to 8,060 (note, however, that Florida and Iowa no longer report COVID case numbers and deaths). The CDC announced that it will stop reporting COVID case numbers, vaccine mandates are disappearing, people are shedding their masks, and it almost seems like life is getting back to normal again. But just because the numbers are improving does not mean that everyone is equally safe.

The epidemiological impact of an infection depends on two factors: (1) its incidence and (2) its fatality rate. Take an infection that has a high incidence but low fatality rate, such as rhinovirus. Prior to the COVID pandemic, the average American adult had 2-3 upper respiratory infections per year and the average child had 8-10 URIs per year. Rhinovirus infections account for about one-third of common colds. The net result is that most Americans have at least one rhinovirus infection every year. Rhinovirus causes rather mild symptoms but rarely causes death. On the other end of the epidemiological impact spectrum is ebola, a viral infection that has a low incidence but has a very high case fatality rate. Ebola is rare outside of Western Africa but if someone gets infected, there is a fifty-fifty chance that they will die and a 100% chance that they will at least get very, very sick. Despite its frequency, we really don’t worry too much about rhinovirus infections but even just one case of ebola in the community can induce widespread panic.

The incidence and fatality rate of COVID-19 falls in-between rhinovirus and ebola. Data from the Nationwide Antibody Seroprevalence Survey indicate that by February 2022, approximately 57% of Americans had been infected by COVID-19, a very high incidence but not as high as rhinovirus. The case fatality rate of COVID-19 is somewhere between 0.5% and 1.0% (the exact number is uncertain due to many infections being asymptomatic). This fatality rate is much higher than rhinovirus but much lower than ebola. Consequently, the degree that we worry when COVID-19 cases are in the community is more than rhinovirus but less than ebola.

The UK Biobank Registry study

However, COVID-19 does not affect all people the same. Since the beginning of the pandemic, it has been clear that age has a huge impact on the mortality rate and the older a person is, the more likely they are to die from an infection. A study from this week’s JAMA confirmed the importance of another risk factor for COVID mortality, namely obesity. The study involved 500,000 people from the general population of the United Kingdom who were enrolled in the UK Biobank registry between 2006 – 2010. People with underlying chronic respiratory disease were excluded from the study. Investigators interrogated the UK national electronic health records for data involving COVID infections, lower respiratory infections, and upper respiratory infections in people in the registry between initial enrollment and February 2021. Subjects were divided into four groups based on body mass index (BMI):

• BMI 14 – 24.9 (normal)
• BMI 25 – 29.9 (overweight)
• BMI 30 – 34.9 (obese)
• BMI 35 – 60 (morbidly obese)

The results showed that in the first year of the pandemic (February 2020 – February 2021), overweight individuals were twice as likely to be hospitalized or die of COVID-19 than those with a normal body mass index. Obese individual were three times more likely to be hospitalized or die and morbidly obese individuals were 4 times more likely to be hospitalized or die. When adjusted for subjects’ age, the increased risks for each BMI category were similar.

The study also looked at non-COVID lower respiratory infections (eg, pneumonia and influenza) and upper respiratory tract infections (eg, common colds) over the entire duration of the registry (average = 11.8 years). The results showed that weight was also a risk for severe infection from colds and pneumonia. During the study period, 2.6% of normal weight individuals were hospitalized or died of lower respiratory infection whereas 3.0% of overweight, 4.1% of obese, and 5.6% of morbidly obese individuals were hospitalized or died. The numbers were similar for upper respiratory infections: 0.22% of normal weight, 0.28% of overweight, 0.32% of obese, and 0.44% of morbidly obese individuals were hospitalized or died of upper respiratory infections.

What does all of this mean for healthcare providers?

The implications of the UK Biobank study is that the degree that we relax COVID precautions depends on how likely you are to become severely ill or die if you get a COVID infection. If you are young, healthy, and have a BMI less than 25, then for all practical purposes, the COVID pandemic is over for you and it is reasonably safe to return to life as usual. However, if you have risk factors such as being overweight or obese, then you should still take precautions because even though the incidence of COVID-19 is dropping, if you are unlucky enough to become infected, then you have a higher chance of dying from it. And the higher the BMI, the greater the risk of dying. In the epidemiological impact spectrum with rhinovirus at one extreme and ebola at the other extreme, being overweight or obese pushes COVID-19 more toward the ebola end of the spectrum than being of normal weight.

So, what should we be telling our overweight and obese patients to do? First, vaccinate. Strongly advise unvaccinated overweight persons to get their initial 2-dose COVID series and be sure that those who are vaccinated are advised to get an updated booster. People who live in the same household as an overweight person should similarly be vaccinated to help prevent transmission to those who are overweight. Given the UK Biobank study results for upper and lower respiratory tract infections, overweight and obese patients should also be strongly advised to get pneumococcal vaccines, influenza vaccines (in the fall), and the new RSV vaccine (for those over age 60). Second, advise obese patients to continue to wear masks in crowded indoor areas. Third, continue to make telemedicine available to those patients who are worried about coming into our offices and clinics.

In 1973, Yogi Berra said of the National League pennant race: “It ain’t over ’til it’s over”. For overweight and obese people, the COVID-19 pandemic is not yet over. There are other people for whom the pandemic is also not over. Those who are over age 65 are 97-times more likely to die of a COVID infection than young adults in their 20’s. Chronic diseases that increase the risk of death from COVID include diabetes, heart disease, COPD, immune suppression, kidney failure, cirrhosis, and HIV. Pregnant people are also at increased risk of serious COVID infection. For these people, masks in high-risk settings are still appropriate.

One of the biggest barriers to mask-wearing is the social pressure to stop wearing them. The awkwardness of wearing a mask when no one else around you is wearing one poses a barrier to those people with obesity and other risks for severe COVID who feel self-conscious wearing masks. As physicians, we can normalize mask wearing by our at-risk patients by wearing a mask ourselves in healthcare settings. Most U.S. hospitals have relaxed mask requirements for healthcare workers, patients, and visitors. Because of this, many physicians and nurses have altogether stopped wearing masks in hospitals or outpatient clinics because they are no longer required to. But the reason we should continue to wear masks in these areas is not because of a lower risk that we will get infected ourselves, it is to signal that it is OK to still wear a mask for our patients with COVID risks such as obesity.

Pandemics don’t just all of a sudden stop one day. Instead, they slowly wind down and then fade away. There will come a time when the COVID pandemic is finally over for all of us but we are not there quite yet. Even though the U.S. hospitalization and death rate is now the lowest in three years, we still had more than 8,000 new COVID hospital admissions and more than 1,000 COVID deaths last week in our country. Just because the pandemic seems over for us individually doesn’t mean that it is over for our patients with risk factors such as obesity.

May 6, 2023

Last week, a little-noticed milestone in the U.S. COVID pandemic occurred – it is the first week that the number of new cases of COVID exceeded the number of vaccine doses administered since the vaccines became available to the general public. It seems that America is ready to be done with COVID and move on. The good news is that both the number of cases and the number of deaths is falling. The bad news is that they are still very high – it’s just that we have developed a national desensitization to the COVID numbers. Last week, 226,618 Americans were diagnosed with COVID, that is enough people to fill Yankee Stadium five times over. In addition, 22,422 people were hospitalized with COVID and 2,290 people died of COVID. To put that in perspective, last week, 4 times more people were admitted with COVID and 10 times more people died of COVID than were admitted and died of H1N1 influenza during the peak week of the 2009 H1N1 influenza outbreak in the U.S. In other words, the best days of COVID are still worse than the worst days of H1N1 influenza. So, what will the COVID picture look like in the next year? We can learn a lot from the epidemiology of other viruses.

 

What we can learn from non-COVID seasonal coronaviruses

Coronaviruses have been infecting humans for as long as there have been humans. There are dozens of different coronavirus species that each have a preferred animal it infects. For humans, there are four seasonal coronavirus strains cause cold symptoms: 229E, NL63, OC43, and HKU1. These coronaviruses are common and cause 15-30% of all common colds. These viruses recur predictably every year as reported by the Public Health Agency of Canada:

There is a striking seasonality to coronavirus infections with most infections occurring in the winter. The graph below shows the average number of coronavirus infections reported by the Public Health Agency of Canada over a 10-year period:

Future COVID seasonality

For the purpose of simplicity, I will use “COVID” (the name of the disease) as synonymous with “SARS-CoV2” (the name of the virus) in this post. At some point in the future, COVID will most likely go the way of other coronaviruses and assume the same seasonal variation with a baseline year-round rate and a rate surge in the winter. We have already seen signs that COVID has a predilection for the winter months in the case rates during the first 3 years of the pandemic. The graph below shows the number of COVID deaths per 100,000 per week in orange and the number of cases per week in blue.

This graph demonstrates that the death rate for COVID peaks about three weeks after the case rate peaks, consistent with the finding that most people who die from the infection do so about 3 weeks after initial diagnosis. There has been a peak in deaths every January (red dashed lines)  followed by a second, smaller peak in deaths every summer (black dashed lines).

Assuming that COVID becomes a seasonal infection, how long will it take to become primarily seasonal? Any answer to this question is speculative but it will likely be several more years before the seasonal epidemiology of COVID resembles that of other coronavirus infections. Until then, it is likely that there will be a moderate or low baseline level of COVID year-round with case numbers increasing in the winter. The main determinant to becoming seasonal is population immunity.

By now, most Americans have either been vaccinated against COVID or have had a COVID infection or both. The result is that most Americans have some degree of immunity. But what we know from the usual seasonal coronaviruses is that immunity fades and it is common for people to get reinfected with the same coronavirus strain. One study found that up to 21% of people get reinfected with the same strain of non-COVID coronavirus within 6 months of the initial infection. Going forward, having immunity from a previous COVID infection or a previous COVID vaccine will not entirely protect a person from getting a future COVID infection. But immunity can reduce the severity of infection, reduce death rates, and reduce transmission. For the population as a whole, compared to people vaccinated with a bivalent booster, unvaccinated people are 3 times more likely to be diagnosed with COVID, 16 times more likely to be hospitalized with COVID, and 10 times more likely to die from COVID. These numbers likely underestimate the protectiveness of vaccines since people most vulnerable to COVID have been the most likely to get the bivalent booster. As an example, people age 65-79 who are are unvaccinated are 14 times more likely to die of COVID than people age 65-79 who are vaccinated with a bivalent booster.

Unfortunately, we seem to have developed a national aversion (or at last indifference) to vaccination. Currently, 92% of adults have received at least one dose of a COVID vaccine but only 79% received a full primary series. Worse, only 20% of adults have received a bivalent booster. The sooner we can overcome our culture of vaccine hesitancy, the sooner we can overcome the consistent high number of non-seasonal COVID cases.

Future COVID mortality rates

Over the past 3 years, one out of every 300 Americans have died of COVID. It is difficult to know the exact mortality rate of COVID infections because we do not know exactly how many Americans have been infected with COVID. Using case numbers reported to the CDC, the average mortality rate since the beginning of the pandemic is 1.63%. This likely overestimates the true mortality rate because many people who get infected either do not get tested at all or do home tests that are not reported to the CDC.  The mortality rate has varied considerably over the past 3 years. In the graph below, the case numbers reported to the CDC are in blue and the mortality rate of infection is in red.

It is quite striking that when the case numbers are high, the mortality rate is low and vice versa. On possible explanation for this curious finding is that when new, more infectious COVID variants emerge, many non-vulnerable people (children and young adults) get infected with these variants at school and in workplaces causing a surge in case numbers. Because these people are often younger or have some degree of immunity from previous infection, they are less likely to die. Over the following several weeks, they then infect vulnerable people who are more likely to die: the elderly, the nursing home residents, and those with chronic diseases. This possible explanation is purely conjecture, however.

Another way of estimating the mortality rate of COVID in the U.S. is to use data from the Commercial Laboratory Seroprevalence Survey. This survey estimated the number of Americans who have had COVID based on COVID antibody tests performed on left-over blood from commercial lab tests. Notably, the antibodies tested for would be produced by COVID infection but not by COVID vaccination. An advantage of using data from this survey is that it picks up those people who either did not get tested for COVID because they had mild or asymptomatic infections and those who did home COVID tests that were not reported to the CDC. As of February 2022, 57.7% of samples contained antibodies against COVID. If we assume that this is reflective of the U.S. population as a whole, then as of February 2022, 57.7% of Americans had been infected by COVID – that translates to 192,306,920 people. At that time, the total number of people reported to have died of COVID was 939,875. Using these numbers, the mortality rate of COVID infection calculates to be 0.5%

From these analyses, it appears that the COVID mortality rate has most likely been somewhere between 0.5% and 1.5% over the course of the pandemic. In the future, the COVID mortality rate will hopefully be lower as more Americans have immunity from repeated infections and from booster vaccinations. However, it is a near certainty that some number of people will continue to die of COVID infections in future years. Decades of experience with influenza has shown us that neither natural immunity (from past infections) nor vaccination immunity prevents all deaths from influenza. There will always be deaths in vulnerable populations such as the elderly, the immunocompromised, the obese, and the diabetic. In these individuals, immunity can reduce but not eliminate the chance of dying from infection.

COVID is a new infection for the human race. A useful lesson from history about new infections is from the European settlement of North and South America in the 15th and 16th centuries. The indigenous peoples of the Americas had never been exposed to infections such as smallpox, a disease that is highly contagious but preferentially kills adults. When the first Europeans arrived, they brought with them these diseases that then rapidly spread throughout the continents. It is estimated that within a few decades of Columbus’s first landing, about 90% of indigenous people had died of infections such as smallpox. After burning through native populations, the smallpox mortality among these populations settled into a lower baseline number. If COVID behaves like smallpox, then it is likely that once COVID burns through the world’s human population that it will settle into a lower steady state mortality rate.

Future COVID hospitalizations

Early in the pandemic, U.S. hospitals were overrun by COVID patients. With no effective treatments, many patients died rapidly and survivors often required prolonged ICU care, lingering in the hospital for weeks. With better treatments and better population immunity, more patients are surviving their COVID hospitalization and they are improving faster, resulting in shorter hospital stays. However, COVID is still resulting in a relatively large number of hospital admissions. The graph below shows new COVID hospitalizations in orange and COVID deaths in blue as reported by the CDC. During the January 2021 surge, 1 person died for every 3 COVID hospital admissions. That ratio has improved so currently, 1 person dies for every 10 COVID hospital admissions.

During the January 2021 COVID surge, the CDC reported that 19% of all U.S adult hospital beds were occupied by COVID patients and 31% of all U.S. adult ICU beds were occupied by COVID patients. A year later, during the January 2022 surge, COVID patients accounted for 23% of adult hospital beds and 31% of adult ICU beds. These two surges put an enormous strain on our country’s hospital resources, particularly our intensive care units. Last week, 3.4% of both adult inpatient and ICU beds as well as 1.5% of both pediatric inpatient and ICU beds are occupied by COVID patients.

Although it is unlikely that we will see the overwhelming spikes in COVID hospitalizations such as we saw in January 2021 and January 2022, it is likely that we will continue to see seasonal fluctuations in hospital utilization as COVID assumes a more seasonal pattern. Because of this, hospitals should start planning now to ensure sufficient hospital beds and staffing for an anticipated spike in COVID admissions next winter. During the most recent COVID surge in January 2023, COVID patients occupied 6.5% of both adult hospital beds and adult ICU beds. Children with COVID occupied 2.4% of pediatric hospital beds and 2.3% of pediatric ICU beds. To be conservative, hospitals should plan on a similar increase in hospital bed and ICU demand next winter.

Future COVID treatments

Experience with other human infections has shown us that science makes incremental advances in treatment resulting in incremental improvement in mortality rates. Examples include tuberculosis, hepatitis C, and HIV. In each of these infections, the earliest treatments were marginally effective but as pharmacologic research advanced, subsequent treatments were better and better. The result is that now, most people infected with these pathogens can either be cured or kept in indefinite remission with current medications.

Over the past three years, we have also seen steady improvement in COVID treatments ranging from the ineffective (azithromycin) to the ludicrous (ivermectin) to the somewhat effective (Molnupiravir) to the highly effective (Paxlovid). If advances in COVID treatment is anything like hepatitis C, HIV, and TB, then we will likely have even better COVID treatments in the future.

Wild cards

Evolution shows that all living things mutate as they reproduce. COVID has been no exception with new variants emerging that are more infectious than the previous variants. The greater the total number of viruses present on earth at any given time, the greater the likelihood of a new variant developing. As worldwide natural and vaccine immunity increases, it is likely that the rate of new variant emergence will slow. This should give vaccine producers more time to create vaccines effective against those new variants, thus improving our ability to stay one step ahead of COVID. Nevertheless, that other variants will arise in the future is a certainty.

One of the reasons that we cannot eliminate COVID from the planet is that it can infect other animals. So far, COVID has been demonstrated to infect more than 30 different kinds of animals. The disease is not as severe or life-threatening as it is in humans but now other animals can serve as viral reservoirs. Even if we could eliminate all human infections today, humans would just get reinfected from deer, pigs, and dogs tomorrow.

Not only will the human race face new COVID variants but we will also likely see new coronaviruses make the jump from other species to ours. This has already happened recently with the coronaviruses that cause MERS (camels) and SARS (bats). There are many, many different coronavirus species with each species affecting different animals. Thus there are different coronavirus species that have been found in cats, dogs, pigs, camels, bats, cows, and chickens. Mutations in any of these coronavirus species can allow them to become infectious to other animals, including humans. The new mRNA vaccine technology now gives us the ability to rapidly develop and distribute vaccines against new coronavirus species that do cross from animals to humans. One challenge is that new vaccines against new viruses require clinical trials to determine vaccine effectiveness and safety. These trials take time and require a large number of subjects. Ideally, we need ways to rapidly predict efficacy and safety without the months required to perform clinical trials.

A future with COVID

It seems clear by now that COVID is not going to go away in the future. It is unrealistic to think that COVID case numbers will steadily go down until COVID drops off the face of the Earth. It will more likely just become one of the many respiratory viruses that humans regularly get infected with. It is likely that there will be a year-round baseline rate and seasonal rate surges. However, we have the ability to control COVID case numbers and case severity by optimizing immunity and by continued research into new medications.

March 6, 2023

I am in an increasingly small minority of Americans who still wear face masks in public indoor areas. And I feel increasingly self-conscious when I’m the only person wearing a mask. But should I feel that way?

I realized that something had changed when I attended the annual American College of Chest Physicians meeting in Nashville last week. When I preregistered a few months ago, I had to attest online that I agreed to wear a mask at all times while attending convention events. When got to the meeting last week, the instructions had changed to “masks are recommended”. In the meeting rooms, I kept track – overall, only 5% of attendees wore a mask. I’m used to this percentage of mask-wearers at the grocery store but at the meeting were hundreds of the country’s pulmonary and critical care physicians who are more intimately familiar with the danger and transmissibility of COVID-19 than any other segment of the U.S. population. Except while delivering a lecture, I wore an N-95 mask the entire time but could not help to think “Does everyone think I’m weird?“.

During the first year of the pandemic, I spend endless hours caring for critically ill COVID patients in our ICU. I intubated them, performed bronchoscopy on them, and pronounced them dead. Back then, everyone wore a mask – in the hospital, in the grocery store, in the airport. And masks worked. Unlike the majority of Americans, I have made it this far through the pandemic without getting infected. I was even part of a CDC prospective study of high-risk healthcare workers and had to get serial blood antibody tests to determine if I got infected caring for COVID patients. All of the tests were negative. When vaccines became available in December 2020, I got my first vaccination at 7:00 AM the first day they were available. And I’ve gotten all 3 booster vaccinations in the first week that they were offered. Other than being 64-years-old, I have no risk factors for severe COVID. So, you’d think I’d be ready to go back to life as it used to be, without face masks.

The thing is, I just don’t want to get COVID.

Yes, I realize that the chances of me dying if I get infected are pretty slim. But they are not zero and besides, there are a lot of other unpleasant complications of COVID that I’d just as soon avoid.

Just because you’re vaccinated doesn’t mean COVID can’t kill you

The COVID vaccines we now have are great. But like most vaccines, they are not perfect. Data from the CDC shows that in August 2022, people who had the primary vaccine series plus 2 or more boosters were 12-times less likely to die of COVID than unvaccinated people. But still, 1 out of every 200,000 Americans died of COVID that month despite being fully vaccinated and boosted. To put that in perspective, if you are vaccinated, you are still 1,500-times more likely to die of COVID than to win the Powerball lottery.

A relative commented to me recently that “COVID is no worse than the flu“. Unfortunately, it is actually worse… much worse. In a typical season, about 25,000 Americans die from influenza. In 2021, 463,000 Americans died from COVID. In other words, Americans were 18-times more likely to die of COVID than die of influenza. And that was despite strict social distancing, masking, school closures, and work-from-home initiatives in 2021. This graph shows the annual deaths from influenza (blue) compared to deaths from COVID (gold).

COVID causes assorted badness other than death

Last month, I was surf fishing in North Carolina. I got to talking to a fellow fisherman who as a chiropractor in his late 60’s who had a bout of COVID shortly after returning from a trip to Ireland. He was fully vaccinated and boosted but still felt wiped out for several days. Weeks later, he still could not taste or smell anything. Personally, I like to taste and smell. I like to be able to tell the difference between a pice of unseasoned tofu and a medium-rare lamb chop. I enjoy a Mendocino pinot noir a lot more than a bottle of Two-Buck Chuck. I don’t want to give those things up. A study from JAMA this summer found that 56% of people infected with COVID have some loss of taste and smell at the time of initial infection. Of those affected, 12% still had loss of taste and smell 2 years after infection. Although the newer variants of COVID are less likely to affect taste or smell than the original COVID, 44% of those infected with Delta and 17% of those infected with Omicron had loss of taste and smell.

Patients experiencing long COVID symptoms have now become common in primary care practices. A study from this month’s JAMA looked at 1.2 million people infected with COVID and found that 6.2% of people have long COVID symptoms – persistent fatigue in 3.2%, persistent respiratory symptoms in 3.7%, and cognitive dysfunction in 2.2%. The average duration of long COVID symptoms was 9 months in those who required hospitalization for their COVID infection and 4 months for those who did not require hospitalization. However, 15% of people with long COVID had symptoms lasting more than 1 year. It seems to me that wearing a mask is a small price to pay in order to avoid fatigue, shortness of breath, and brain fog.

Although vaccination greatly reduces the chance of severe COVID requiring hospitalization or ICU care, breakthrough infections are common in vaccinated people as well as those with immunity from previous infection. A study in the New England Journal of Medicine found that breakthrough infections in vaccinated people typically caused fever, muscle aches, loss of taste/smell, and cough. These symptoms lasted more than 14 days in 31% of people and 23% of people had to take off more than 10 days of work due to symptoms. In short, it is no fun to have a breakthrough COVID infection even though you will probably survive it.

The CDC’s COVID dashboard indicates that the number of COVID cases in the U.S. is falling – only 260,000 new infections were reported last week – down from 5.6 million new cases nine months ago during the third week of January 2022. However, the current prevalence numbers underestimate the true number of new covid infections because many people either choose to not be tested or test themselves using over-the-counter COVID home tests. Either way, these cases do not get reported to local public health departments and are thus not included in the CDC’s data. The bottom line is that tens of thousands of Americans are still getting COVID infections every day.

The social pressures to wear masks

The psychology of masking and unmasking is complex and was nicely described in an essay by blogger JTO, PhD. The various psychological concepts that contribute to people disliking masked people when they themselves are not wearing masks include cognitive dissonance, confirmation bias, psychological reactance, and hostile attribution bias. The net effect of these is strong peer pressure to conform when those around you are not wearing masks.

Social psychologist Dr. Wendy Treynor has proposed a theory of peer pressure called “identity shift effect”. According to this hypothesis, a person’s internal harmony is disrupted a person fails to conform to a group standard resulting in a threat of social rejection. In order to eliminate this threat, the person changes their behavior to conform to the group but in doing so, causes internal conflict because that person has now violated their own code of conduct. To eliminate this internal conflict, the person undergoes an “identity shift” and adopts the group’s standards as their own, thereby eliminating internal conflict and restoring internal harmony. The net result is that the person adopts a new attitude.

For example, if you go to a restaurant wearing jeans because you don’t like getting dressed up and everyone else in restaurant is wearing an evening dress or a suit, you will experience a great deal of psychologic disharmony. The next time you go to the restaurant, you wear a dress or a suit in order to avoid the disharmonious feelings, even though in the past, you didn’t like wearing formal attire.

As human beings, we strive to be accepted by groups of other people. Even non-conformists are often trying to conform to the behavior of other non-conformists to prove that they are just as much of a non-conformist as the other non-conformists.

When you wear a face mask in a store full of unmasked customers or in a church full of unmasked parishioners, you start thinking: “Do they think I’m weak?” or “Do they think I’m a coward?” or “Do they think I’m the one who is contagious?” Fortunately, wearing a mask is not as much of a violation of social norms as wearing a MAGA hat to an ACLU convention or wearing a Cincinnati Bengals jersey in a Pittsburgh sports bar. But nevertheless, there is increasing peer pressure to take one’s mask off.

The advantage of being old

One of the wonderful things that happens when you retire is that you now have the luxury of doing what you want to do rather than what everyone else is doing. Even so, I find myself sometimes apologizing for wearing a mask when no one else is. I’ll sometimes offer up excuses such as “Sorry, I worry too much because I’m a senior citizen” or “I’m going to visit my pregnant daughter and don’t want to risk exposing her“. Most people who I pass in a store or airport just think I’m weird. But I can live with that because I plan to enjoy a healthy life for many more years. Life is just too short to waste days or weeks of it being sick. So, I’m OK with being weird.

October 28, 2022

There are two ways to become immune to COVID-19: either from previous infection (natural immunity) or from vaccination. But is one better than the other? Many people believe that anything “natural” is better than “artificial” and consequently some pundits, influencers, and bloggers advocate for for natural immunity over vaccination immunity. The COVID Nationwide Antibody Surveillance Survey reported that by February 2022, 58% of Americans had been infected with COVID-19 and thus have some degree of natural immunity. The most recent CDC vaccination data shows that 80% of Americans have received at least 1 dose of a COVID vaccine and 68% have received 2 doses with resultant vaccination immunity. Therefore, most Americans have some degree of immunity one way or the other. Employers and governments are now grappling with whether to mandate vaccination or proof of previous infection as workers return to in-person workplaces.

 

Immunology 101

At the risk of oversimplification, there are two main components of our immune systems – cellular and humoral. Cellular immunity involves T-lymphocyte cells that help fight infection. Humoral immunity involves immunoglobulins (antibodies) that help fight and prevent infection; immunoglobulins are produced by B-lymphocytes. There are five types of immunoglobulins but the three types that are most important for preventing viral infection are IgG, IgM, and IgA. All three of these types of antibodies can be found in the bloodstream but mostly IgA is found on the surface of respiratory cells, such as in the mucus that lines the airways and nasal passages.

When a person gets infected with a virus, the virus uses special molecules on its surface that can bind to cells and then slip inside those cells. These surface molecules are like keys that open the cells allowing the virus to get in. Once inside of a cell, the virus takes over the cell and causes the cell to start to manufacture thousands of copies of the virus (its like what happened to people in the movie Alien). The cell then dies and releases all of the newly manufactured viruses that can then infect more cells.

Once infected with a virus, the body’s immunologic response is to create antibodies to pieces of the virus. Antibodies first start to be produced by B-lymphocytes 5-7 days after an infection with the first antibodies being IgM. Within days to weeks, some of the B-lymphocytes switch to making IgG plus IgM antibodies and the levels of IgM antibodies quickly fall. Over time, the quantity of IgG antibodies in the bloodstream also gradually falls but when the body is re-infected with the same virus, memory B-lymphocytes that had previously been “taught” to make specific antibodies against that virus can ramp up production very quickly resulting in high IgG levels in 1-2 days.

Antibodies fight viral infections in three ways. First, they bind to molecules on the surface of viruses that attach to cells. This is like covering up the “key” so that the virus cannot attach to and get inside of cells. Second, when antibody-coated viruses do get inside of a cell, that cell uses the antibodies as a signal to the rest of the immune system that it is infected, causing other immune cells to attack and kill the cell before it can produce new viruses. Third, when viruses are coated with antibodies, immune cells called macrophages recognize them and “eat” the viruses. The macrophages then digest the viruses and destroy them.

Respiratory viruses, like COVID-19, are first inhaled into the nose and respiratory tract where they get stuck in the mucus that lines those passages. The viruses then infect airway cells and eventually get into the bloodstream where they are carried throughout the body and can infect cells in the heart, liver, brain, muscles, etc. IgA in the mucus of the airways (mucosal immunity) is the first line of defense when a person inhales COVID-19 viruses. IgG in the bloodstream (systemic immunity) is the next line of defense once the COVID-19 virus gets past the airway cells and invades the body.

Antibodies do not always prevent viruses from getting into the body, they just prevent viruses from getting out of control. Since the memory B-cells take 1-2 days to ramp up antibody production, the virus will have a 1-2 day head start to begin to infect cells and reproduce. However, in those first 1-2 days of infection, there are not too many viruses in the body and so a person usually has no symptoms early on (this is the incubation period). Thus neither natural nor vaccination immunity necessarily prevents viruses from getting into the body, they primarily prevent the infection from becoming severe and hopefully prevent you from dying of the infection. In this sense, a viral infection is similar to a mouse infestation in your house – mouse traps in your kitchen can stop the mice from reproducing and eating all of the food in your house but they won’t prevent the mice from getting into the house in the first place.

Because antibodies do not usually prevent viruses from getting into the body and starting to initially reproduce, people with either natural or vaccination immunity can still be contagious to others in those first few days after a virus gets into their body, even though they have no symptoms. The good news is that the number of viruses in the air that they exhale is low and the lower the number of viruses in the air, the less likely it is that someone else breathing that air will become infected.

When a person is infected with COVID, B-lymphocytes in the airways are stimulated to produce anti-COVID IgA antibodies that is released into the airway mucus. Once the COVID virus gets into the bloodstream, blood B-lymphocytes are stimulated to make anti-COVID IgA, IgM and IgG antibodies that are released into the blood. These antibodies recognize different molecules on the surface of the virus and because there are lots of different surface molecules, there are lots of different types of IgA, IgM, and IgG antibodies produced. In other words, COVID-19 infection results in many different types of IgG antibodies. This is different than vaccination immunity.

When a person is vaccinated against COVID, the vaccine is injected into the muscles and then the vaccine gets into the bloodstream. As a result, most of the B-lymphocytes that get stimulated are bloodstream lymphocytes and not airway lymphocytes. These are the lymphocytes are mainly responsible for producing IgM and IgG. B-lymphocytes in the blood also produce some IgA that stays in the blood but since the airway B-lymphocytes are not stimulated, very little airway mucus IgA gets made. Vaccination immunity to COVID also differs from natural immunity because of the types of IgG that are produced. The original Anti-COVID vaccines only produce antibodies against one part of the “spike protein” which is a the molecule on the surface of the virus that the virus uses to attach to cells. If the virus mutates and the spike protein molecule changes shape (as happened with the Omicron variant), then the antibodies produced from vaccination immunity may not recognize this new shape and may be less effective. The new booster COVID vaccines are bivalent and produce antibodies against a part of the spike protein on the original COVID virus and also against a part of the spike protein on the newer Omicron variant.

Natural COVID immunity

Natural immunity to COVID refers to immunity caused by previous infection by COVID. Some people (for example, quarterback Aaron Rodgers) falsely claim “natural immunity” from homeopathic treatments but this is NOT natural immunity. The only ways to develop immunity to COVID is to either have previously been infected by COVID or be vaccinated against it. Because of the different ways that natural immunity and vaccination immunity affect the body’s immune system, both forms of immunity have advantages and disadvantages.

Advantages of natural immunity:

1. Bloodstream IgG production. Human B-lymphocytes have been making IgG in response to infection by various viruses for hundreds of thousands of years and our B-lymphocytes have gotten very good at it.
2. More types of IgG antibodies. Because infection with COVID results in many different types of antibodies against many different parts of the surface molecules of the virus, there is a better chance that some of those antibodies will still work against the virus if a new variant arises with a different shape to just one of the surface molecules. A January 2022 study in the MMWR found that prior to the emergence of the Delta variant, people who were vaccinated were less likely to become infected than people who had previously had a COVID infection but after Delta emerged, those with a previous COVID infection were better protected against future infection than those who were vaccinated. Similarly, a study published two months ago found that previously vaccinated people were 13-times more likely to have a breakthrough infection with the Delta variant than previously infected but unvaccinated people.
3. More mucosal IgA antibodies. Because the COVID virus first stimulates airway B-lymphocytes, those lymphocytes can “learn” to make anti-COVID IgA that gets into the mucus of the nose and airways. Since mucus IgA is the first line of defense, if a person gets re-infected with COVID at a later time, that mucosal IgA can kill off the viruses before they can get into the bloodstream.

Disadvantages of natural immunity:

1. Lower levels of IgG antibodies. Our immune systems are like muscles, they work best when they continue to train. The more you repstimulate the humoral immune system, the stronger it gets. A COVID-19 infection results in a one-time stimulation to the immune system and this can result in lower antibody levels than in a person whose immune system is stimulated by 2 doses of a vaccine followed by booster doses. Some people produce little or no antibodies after infection. A study from September 2021 found that only 64% of people with severe COVID infections causing ARDS had detectable IgG or IgA antibodies after they recovered from infection.
2. You only get natural immunity if you survive the infection. More than 1 million Americans have died of COVID infection. These people’s immune systems never got a chance to make antibodies for long-term protection. Even for those who survived the initial infection, the results of the infection are usually feeling really, really bad for a few days and often having long-term loss of taste and smell. Furthermore, long-COVID symptoms occur in one out of every five people infected. Thus, the cost of natural infection is very high.

Vaccination immunity

Because of the different way that COVID infection and COVID vaccination affect the immune system, there are different advantages and disadvantages with vaccination immunity.

Advantages of vaccination immunity:

1. Bloodstream IgG production. All vaccines work by teaching the body’s immune system to make antibodies and the COVID vaccines are no different.
2. High levels of IgG antibodies. The initial vaccination consists of 2 dose of the vaccine, given 3 weeks apart. This results in the humoral immune system being stimulated twice, as opposed to actual infection with COVID which only stimulates the immune system once. Getting booster vaccinations results in a third, fourth, and fifth time that the immune system gets stimulated. This “trains” the immune system to get very good at producing anti-COVID antibodies. A study from July 2022 found that antibody levels after mRNA vaccine administration were higher and lasted longer than antibody levels after COVID infection.
3. Better protection if variants do not occur. A study from August 2021 found that prior to the emergence of the Delta variant, people who had been infected with COVID but not vaccinated (natural immunity) were 2.3-times more likely to become reinfected than people who were vaccinated but never previously infected (vaccination immunity).
4. You don’t have to get sick to become immune. Although it is true that COVID vaccines can cause side effects, scientific studies as well as my own personal experience show that the side effects of vaccination are way, way, way less than the symptoms of a COVID infection. I have now had 5 different COVID vaccinations and I would take the side effects of all of them combined over even a mild case of COVID infection any day.
5. The vaccines won’t kill you. The vaccines are safe. A study of 11 million people vaccinated with the Pfizer or Moderna vaccines found that there was no increased risk of mortality by getting vaccinated. On the other hand, about one out of every 100 people who get a COVID infection die from the infection. Even those people who survive the initial COVID infection are 233% more likely to die in the year after infection than people who do not get infected based on a study published last December. To put the mortality numbers in perspective, you are 3 million times more likely to die from a COVID infection than to have a winning Powerball ticket.
6. Vaccination after a COVID infection improves immunity. A study from July 2022 found that the effectiveness of infection was 46%, the effectiveness of three doses of a vaccine was 52% but the effectiveness of infection plus three doses of a vaccine was 77%. This is sometimes called “hybrid immunity”.

Disadvantages of vaccination immunity:

1. Single type of IgG antibody. Since the original vaccines resulted in IgG against a specific part of the COVID spike protein, if there is a change in that protein, then the antibodies may not work as well. This was a particular problem with the Omicron variant that caused infection in many people who had been vaccinated earlier. However, even though the vaccines do not work as well if the virus mutates, they do still work and as a result, vaccinated people who get a COVID infection will have milder cases of the infection than unvaccinated people. The newer booster vaccines are bivalent and result in production of two types of antibodies which improves the effectiveness against variants.
2. Lower mucosal IgA levels. Because the airway B-lymphocytes are not strongly stimulated by vaccination, there is lower anti-COVID IgA in the mucus of vaccinated persons compared to those who have previously had a COVID infection. Thus vaccinated persons may not have as strong of a first-line defense against infection. A study from 2021 found that vaccination causes high levels of IgA and IgG in the bloodstream but little to no IgA in the saliva. A study from July 2022 found that infection with the Omicron variant of COVID resulted in 10-times more IgA in respiratory secretions (bronchoalveolar lavage fluid) than vaccination. A second study from October 2022 also found that people previously infected with COVID had higher mucosal IgA levels than vaccinated but not previously infected people.

What does all of this mean?

So, is natural immunity better than vaccination immunity? Well, it depends… We can draw several conclusions from all of the above findings:

• If variants do not emerge, vaccination immunity is better than natural immunity.
• The more boosters a person gets, the better their protection.
• If variants emerge, natural immunity may be stronger than vaccination immunity until new vaccines are developed against those variants.
• Natural immunity plus vaccination immunity (hybrid immunity) gives the strongest protection.
• Although early studies are promising, it is too early to tell if the new boosters that cover Omicron will be better than natural immunity.

For employers trying to decide about whether to mandate vaccination for employees, it is hard to defend a position that vaccination is superior to natural immunity in every case. For example, a person who received 2 shots of the original mRNA vaccines in 2021 may have less immunity than a person who survived an Omicron infection in 2022. Instead of vaccination mandates, a better approach would be immunity mandates by having employees either provide documentation of vaccination or documentation of past infection. However, Americans as a society dislike mandates of any kind and so rather than mandates, it may be better to link immunity documentation to health insurance premium prices, life insurance premium prices, or other employment fringe benefits.

My recommendation is that everyone should get vaccinated and then get as many boosters as you can, including the newest booster that covers Omicron. In theory, immunity from these new boosters should be better than having natural immunity alone. If you have previously had a COVID infection (and are still alive), then get vaccinated and also get the new booster… you can relax with the knowledge that you will then probably have the best immunity against COVID on the planet. We have come to a point in the pandemic where having no immunity (neither natural nor vaccination immunity) is socially irresponsible and only prolongs the pandemic for the rest of us.

October 20, 2022