With CNN reporting April 15 that 5,800 fully vaccinated Americans have contracted the novel coronavirus – a figure that may underestimate the true number, inclusive of asymptomatic infection – people who have received both doses of either the Pfizer/BioNTech or Moderna product may be asking themselves whether they are truly protected.

Note: As neither the Pfizer/BioNTech BNT162b2 nor the Moderna mRNA-1273 is a traditional vaccine, but a set of mRNA instructions that tell the recipient’s body to make the S protein in order to spur antibody production against the protein, we refer to them as “products” rather than “vaccines” in this piece. The historically accepted definition of a vaccine is a “suspension of weakened, killed, or fragmented microorganisms or toxins or of antibodies or lymphocytes that is administered primarily to prevent disease.” Traditional injections like the measles-mumps-rubella series made by Merck are vaccines.

Titer tests available

for COVID-19

Lab testing firms have stepped up, offering Titer tests to those with concerns. Any Lab Test Now!, with locations across the country, including on Tilghman Street in Allentown, is running a campaign called “Test My Shot.” Patients can schedule a simple blood draw – no fasting required – so that a sample can be tested to measure the “titers” or levels of antibodies against the spike (S) protein that the Pfizer and Moderna products induce the body to produce.

Titer tests are not new. They have historically been used to inform doctors’ advice on whether a previously infected person or a person who has received some, but not all, doses of a series of shots will require additional boosters to develop sufficient antibody levels to protect him from disease. The key concept is called “correlates of protection.” Simply put, these correlates are derived by charting antibody levels for a specific virus against a person’s odds of contracting that virus. However, even for vaccines that are licensed (rather than emergency-authorized, like the coronavirus products), the data on correlates of protection are generally imprecise.

Protection correlates difficult to determine

Why don’t we know how many antibodies a person needs to be immune to a disease? Part of the problem is the paucity of data. Few countries regularly perform nationwide titer tests for infectious diseases. (Australia is a notable exception. Its regular measles seroprevalence survey is described in this 2018 article in the journal Vaccine: https://pubmed.ncbi.nlm.nih.gov/29269156/).

Another issue is that although vaccines have been administered in the United States for nearly 100 years, most Americans have natural immunity – from actual infection – to many of the diseases currently deemed “vaccine-preventable.” Writing about measles in Vaccine in 2019, a multinational team of researchers explain, “No country has yet experienced the epidemiologic situation of having an entire population immune only through immunization.” In other words, Baby Boomers’ natural measles infection prior to the introduction of the vaccine in the 1960s may be partially responsible for the extremely low incidence of measles among younger, vaccinated Americans. When the Baby Boom generation dies, better estimates of correlates of protection for many diseases will be possible.

Work is underway to determine correlates of protection for the novel coronavirus. As reported April 28 by National Public Radio, projects to find these correlates are being undertaken at both Oxford University in the UK, led by Prof. Helen McShane, and the US Biomedical Advanced Research and Development Authority (BARDA), led by Chris Houchens and biostatistician Peter Gilbert. However – due in part to the small number of vaccinated individuals who have been infected – there is not enough data to generate a reliable antibody “cutoff” number.

Immunity wanes

over time

Added to the lack of reliable correlates of protection is the fact that all immunity-naturally acquired through infection or vaccine-induced-wanes over time, so a person who has sufficiently protective antibody levels today may be vulnerable again. The time it takes for antibodies to wane varies by disease. As reported in Science Magazine in in 2019, for example, a flu shot that is nearly 35 percent effective just after being administered is nearly worthless after 150 days. This fact led Dr. Stanley Plotkin, who worked on the rubella vaccine in the 1960s, to get two flu shots each winter, 90 days apart.

Other vaccines induce protection that lasts longer. For example, people produce significant levels of antibodies against the bacterium that causes tetanus many decades after vaccination. Duration of protection varies by the virus or bacterium involved, as well as by the individual, so it’s hard to predict. Dr. Plotkin told “Science Magazine” reporter Jon Cohen, “We simply don’t know what the rules are to inducing long-lasting immunity. For years, we were making vaccines without a really deep knowledge of immunology. Everything of course depends on immunologic memory, and we have not systematically measured it.”

With the novel coronavirus, today’s public health experts are particularly concerned about elderly people, whose immune response is generally less robust than that of younger individuals. Speaking at Harvard University’s Chan School of Public Health on Apr. 26, Asst. Prof. Michael Mina noted that by the fall or winter of 2021, older Americans who received Pfizer or Moderna shots in the winter of 2020-21 may be sickened in a new wave of infections.

Assistant Professor Mina seemed to believe that the United States would remain on a wartime footing for the foreseeable future, saying, “We have to be very, very careful … [about] that narrative that it’s ending… I think it’s important for us today to start talking about and getting society conditioned that that is a real likelihood so that we don’t have an outcry when fall and winter come.”

Variants introduce a new wrinkle

Both Pfizer and Moderna are building up capacity to produce booster shots for previously vaccinated individuals. Both companies are also developing new products to induce recipients to produce variations on the S protein, based on dominant variants in circulation at different points in the future.

In a Feb. 25 press release, Pfizer and German partner BioNTech announced, “In order to be prepared for any potential future strain changes, Pfizer and BioNTech are in ongoing discussions with regulatory authorities, including the U.S. Food and Drug Administration (FDA) and the European Medicines Agency, regarding a registration-enabling clinical study to evaluate a variant-specific vaccine having a modified mRNA sequence. This study would use a new construct of the Pfizer-BioNTech vaccine based on the B.1.351 lineage, first identified in South Africa. This could position the companies to update the current vaccine quickly if the need arises to protect against COVID-19 from circulating strains.”

Moderna made a similar announcement Jan. 25.

“The Company is advancing an emerging variant booster candidate (mRNA-1273.351) against the B.1.351 variant first identified in the Republic of South Africa. The Company is advancing mRNA-1273.351 into preclinical studies and a Phase 1 study in the U.S. to evaluate the immunological benefit of boosting with strain-specific spike proteins. Moderna expects that its mRNA-based booster vaccine (whether mRNA-1273 or mRNA-1273.351) will be able to further boost neutralizing titers in combination with all of the leading vaccine candidates.”

Both Pfizer and Moderna expect to face even lighter scrutiny from the FDA for these variant products, following a pathway similar to that of annual updates to flu vaccines. Additionally, Pfizer and Moderna acknowledge in their press releases that neither company’s product has been approved or licensed by the FDA, but has been authorized for emergency use for the duration of a declared emergency.

Many unknowns

Right now, a titer test can tell you what level of antibodies are circulating in your body against the S protein from the March 2020 coronavirus strain. Until the work at Oxford or BARDA is complete, we won’t know how high these antibody levels have to be to prevent symptomatic infection. Given that it will be a very long time – perhaps a century, if ever – before the United States population has only vaccine-induced immunity to the novel coronavirus, these correlates of protection will only be estimates during the our lifetime.

We also don’t know how long antibody production lasts without a booster dose, how often booster doses will be required to maintain any particular level of antibody production, or how quickly the S protein mutates enough to necessitate restarting the shot process.

Ultimately, vaccines are not designed to reduce any individual’s risk of illness to zero. The theory behind vaccination campaigns – based on a theory of naturally acquired “herd immunity” – is that if enough people are unlikely enough to become infectious with a particular pathogen, the spread of the pathogen will be substantially reduced. It remains to be seen how many people are enough, and how unlikely is unlikely enough, for this novel virus.