What We Can Learn From The COVID Seroprevalence Study

This week, the latest results of the Nationwide COVID-19 Infection-Induced Antibody Seroprevalence (Commercial laboratories) Study was released. These results estimate the percentage of the population of each state that has been infected with COVID-19 as of the end of December 2022. The results are quite remarkable and indicate that there has been enormous variation in the frequency of the infection among the states and among different age groups.

The commercial laboratories seroprevalence study is done monthly and uses left-over samples of blood drawn by commercial laboratories for routine blood tests. Patients getting tested specifically for COVID-19 are excluded. The antibodies detected in this study are directed against the nucleocapsid antigen and these antibodies are only produced from actual infection by the virus. The COVID vaccines produce antibodies against the spike protein antigens and these are not measured by the tests used in the commercial laboratories seroprevalence study.

Limitations of the seroprevalence study

The methodology of the seroprevalence study was published in the April 2021 edition of JAMA Internal Medicine. Because the samples are anonymous, there are several potential limitations of the study that could affect the prevalence results:

  1. Healthy adults and children are less likely to have routine blood tests. Therefore, people with chronic diseases are more heavily represented in the samples. If patients with chronic diseases are also more likely to get infected with COVID-19, then the results may overestimate the percentage of the population previously infected with COVID.
  2. Because the results depend on blood tests drawn in December 2021 from live patients, those people who died of COVID-19 prior to December 2021 are not included. This results in the study underestimating the percentage of the population infected since the beginning of the pandemic. This limitation can be corrected by adding the number of COVID deaths to the seroprevalence data to get total infection data (see the analysis later in this post).
  3. People who do become infected with COVID-19 frequently have lingering symptoms (“long-haulers”) that could prompt their physicians to order various blood tests and this could result in the the seroprevalence study overestimating the percentage of the population previously infected with COVID.
  4. Because antibody levels decline over time, it is likely that some patients who had COVID-19 infection early in the pandemic no longer have detectable antibodies against the virus. This could result in the study underestimating the percentage of the population infected since the beginning of the pandemic.
  5. People with less access to healthcare due to socio-economic disparities and people who choose to avoid healthcare are less likely to have routine blood tests drawn. These groups include the uninsured, those who choose to not get vaccinated, residents of rural areas, and the poor. These groups are known be at higher risk of becoming infected with COVID-19. This could result in the study underestimating the percentage of the population infected since the beginning of the pandemic.
  6. The number of blood tests from North Dakota, South Dakota, and Wyoming was too low for statistical analysis and so the study does not include seroprevalence rates from these three states.

Despite these limitations, compared to other epidemiology studies, the commercial lab seroprevalence study gives us the most accurate estimate of the percentage of the U.S. population that has had a COVID-19 infection. First, it is likely that the limitations above that result in overestimation are balanced out by those limitations that result in underestimation of the number of infections. Second, it is likely that the above limitations apply more-or-less equally among different states, allowing reasonably accurate comparison of the rates of infected between different states.

Differences between states

The CDC regularly reports on the total number of infections (based on nasopharyngeal PCR or rapid antigen tests) per 100,000 population since the pandemic began. These results indicate a low of 12.2% of the population in Maine to a high of 30.2% of the population in Rhode Island. However, these results depend on COVID test results reported to local health department and underestimates the true number of infections because (1) many infected people are asymptomatic and do not get tested, (2) many infected people use retail COVID tests with results that are not reported to the health department, and (3) many symptomatically infected people choose to not get tested. For these reasons, the seroprevalence studies offer a more accurate measure of the true rates of infection. The commercial lab study indicates enormous variations in the rate of COVID among the states and territories from a low of fewer than 1 out of every 10 people to a high of nearly 1 out of every 2 people

States with the lowest rates of infection. 15 states and territories had antibody prevalence rates of less than 30% of their population. The lowest rates were in Puerto Rico (9.7% of the population previously infected) and Hawaii (11.1% of the population previously infected. Living on an island was protective against becoming infected. Rhode Island (which is not really an island) is notable because by nasopharyngeal testing, it has had the highest rate of infection in the U.S. but by seroprevalence testing, it has had one of the lowest rates of infection. Rhode Island has the third highest vaccination rate (78.1% of its population) in the country. It is likely that for Rhode Island, the seroprevalence data is more accurate than the case rates determined by nasopharyngeal testing. The common feature of these 15 states & territories is that they all have high COVID vaccination rates with greater than 65% of their population fully vaccinated. We’ll give these states a grade of “A” for controlling the pandemic.

States with intermediate rates of infection. 19 states had rates of infection between 30-40% of their populations. We’ll give these states a grade of “C” for controlling COVID-19. With a United States overall average of 33.5% of the population previously infected, these states performed about average overall.

States with high rates of infection. 15 states had antibody prevalence rates above 40%. Iowa and Montana tied for the highest rate of infection with 47.7% of their population having been infected during the pandemic. These states also have low COVID vaccination rates with all of these states having fewer than 65% of their population fully vaccinated. This provides additional evidence that vaccination prevents infection. We’ll give these states a grade of “F” for controlling the pandemic. Lamentably, my own state of Ohio is the 4th worst in the country for antibody prevalence. The tone for Ohio’s response to COVID-19 was set early in the pandemic when AR-15 wielding anti-maskers protested in the front yard of our state’s Director of Public Health when she was trying to get her children off to school… she resigned, leaving Ohio with no health department director for months.

Differences between genders

Overall, there was no difference in the antibody prevalence among men (33.2%) and women (33.8%). In most states, the difference in rate of infection between men and women was less than 5 percentage points. However, three states had gender differences of more than 6 percentage points:

  • Pennsylvania: 30.3% of men and 39.6% of women
  • Indiana: 37.4% of men and 45.0% of women
  • Montana: 51.4% of men and 43.9% of women

Differences by age

There was a striking relationship between age and seroprevalence of COVID-19 antibodies with the study indicating that far more younger Americans have been infected than older Americans:

In this table, the second column from the left is the seroprevalence of COVID-19 antibodies indicating past infection for each age group. The third column is the percentage of the population in each age group that has died of COVID since the pandemic began. The fourth column is the sum of the seroprevalence plus the percentage of each age population that died of COVID; this column gives a more accurate number of the total percentages of Americans in each age group that became infected with COVID and then either lived (seropositive group) or died of COVID (% died group). Even correcting for the fact that most of the deaths from COVID occurred in people over age 65, it is still clear that younger Americans were more likely to become infected than older Americans.

The causes for the age differences in infection rates is likely multifactorial. Younger people were more likely to have employment or school exposures whereas retired older people were more likely to be able to isolate at home during the pandemic. Younger people tend to live in larger households with children and adults together whereas older people are more likely to live with only their spouse or to live alone. Older Americans are more likely to be vaccinated than younger Americans. Older people are also more risk-adverse than younger people when it comes to masking and social distancing in public areas.

So what does all of this mean?

There are two ways to get immunity to COVID-19: (1) get vaccinated or (2) get infected. Immunity causes a reduction in the chance of subsequent infection (or re-infection). Immunity causes a greater reduction in the chance of hospitalization from infection (or re-infection). And immunity causes an even greater reduction in the chance of dying from infection (or re-infection).Which type of immunity is better? It appears that vaccination gives better immunity than past infection. But even if the two give equivalent immunity, the risk of dying from a COVID vaccine is negligible whereas the risk of dying from a COVID infection is 1 out of 85 – getting immunity from vaccination is far safer than getting immunity from infection.

Epidemiologists talk of “herd immunity” when enough of the population has immunity from either vaccination or past infection. Most epidemiologists now believe that between 75% and 90% of the population must have immunity in order to bring an end to the pandemic by herd immunity. Because people can get re-infected with COVID, the coronavirus will probably never go away but if we achieve herd immunity, we should be able to keep the number of new infections relatively low. More importantly, herd immunity should keep the number of hospitalizations and deaths extremely low. In other words, the goal of herd immunity is not to prevent all COVID infections but instead to prevent COVID hospitalizations and COVID deaths. Indeed, the current data indicates that most of the people who are hospitalized with COVID are unvaccinated and almost all of the people who are die of COVID are unvaccinated.

Currently, we know that 64% of the U.S. population has immunity by being fully vaccinated. We know that 33.5% of the U.S. population has immunity by having had a past COVID infection. What we do not know is to what extent these two populations overlap; that is, how many people who have had a COVID vaccination also had a COVID infection (either before or after they got their vaccination). Another way of looking at this is that we do not know how many people have immunity from either vaccination or past infection. Certainly more than 64% of the U.S. population has immunity but probably less than 90% has immunity.

To forecast what COVID may look like in future years, consider rhinoviruses. They cause 1/3 to 1/2 of all common colds. Given that the average person gets 2-3 colds per year, most people become infected with a rhinovirus every year and nearly everyone has been infected at least once by adulthood. Because re-infection with COVID can occur, it is likely that COVID will continue to circulate in the community for the indefinite future. Eventually, nearly everyone will have either been infected or been vaccinated. At that point, hospitalization or death from COVID should become uncommon. In other words, COVID won’t go away but it won’t kill you in the future.

The primary goal of medicine is to prevent people from becoming severely ill or dying from infections. A more aspirational (but usually unobtainable) goal is to prevent all infections, even mild ones. As long as there are people with weak immunity against COVID (either because they are not vaccinated or they have not yet been infected), then COVID will continue to cause hospitalization and death.

Therefore, our realistically obtainable goal in public should be to prevent severe COVID infection and prevent death from COVID. In that sense, we are reaching a point where we should not be looking at vaccine mandates but instead be looking at immunity mandates. In other words, instead of requiring all of a business’s employees to be vaccinated, we should be requiring all employees to either be vaccinated or have antibodies indicating past infection.

Immunity mandates should become our new public health doctrines – for our workplaces, our schools, and our military. For me personally, sign me up for a second booster when they become available… but I’ll pass on getting a COVID-19 infection to keep my immunity up.

February 5, 2022

By James Allen, MD

I am a Professor Emeritus of Internal Medicine at the Ohio State University and former Medical Director of Ohio State University East Hospital