How many people have been infected with COVID-19 to date? New evidence suggests that answering this question may be more challenging than previously thought. Currently, investigators conduct serological surveys, testing blood samples for antibodies against the nucleocapsid protein (anti-N Abs) to estimate what percentage of people have had a prior COVID infection. But a new study suggests that this form of testing may be undercounting prior infection. Among participants in a clinical trial who were tested for COVID-19 using a polymerase chain reaction (PCR) test, only about 40 percent of vaccinated participants who had a PCR confirmed SARS-CoV-2 infection had a positive anti-N Ab subsequently. Results were recently published earlier this month in Annals of Internal Medicine .
“This was a surprise — previously, the thinking was that infection with SARS-CoV-2 would leave behind an immunologic footprint that we could measure through serologic studies and accurately estimate prior infection, both at the individual and population levels, similar to how we use Hepatitis B virus core antibody to assess prior Hepatitis B virus infection,” said corresponding author Lindsey Baden, MD , of the Division of Infectious Diseases at Brigham and Women’s Hospital . “But our study shows us that we need to take vaccination status into account.”
To evaluate how well serological testing for anti-N Ab captured rates of prior infection, researchers evaluated data from a phase 3 randomized, double-blind, placebo-controlled vaccine efficacy trial of the mRNA-1273 COVID-19 vaccine (Moderna). During the trial, half of participants received the mRNA-1273 vaccine and half received a placebo. All participants were tested for SARS-CoV-2 with a PCR test if they showed symptoms of possible COVID illness. All participants had systematic serial blood sampling during the study.
Baden and colleagues evaluated blood samples for about 700 participants with PCR-confirmed illness during the blinded phase of the trial (through March 2021). They found at the end of the blind phase of the trial that among placebo recipients, 605 of 648 (93 percent) were positive for anti-N Ab. But among those who were vaccinated, only 21 of 50 (40 percent) had anti-N Ab.
The authors note that their sample size was small and data were collected before the Delta and Omicron waves of the pandemic, but their findings may have important implications for individuals and public health officials who are interested in prior infections.
“Diagnosing previous infection isn’t simple at the individual or population level,” said Baden. “But it’s important to keep in mind that failure to develop this footprint of anti-N Ab does not mean failure to develop a robust immune response as evidenced by the substantial clinical protection afforded by vaccination. In fact, it may be just the opposite. We know that people who have received mRNA vaccines tend to have fewer and milder infections. And that’s the goal: we want people to have enough immunity so that they won’t get sick. But these data suggest it may be more challenging to capture a history of prior infection with tests that are looking for this marker.”
Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M22-1300.
Funding: This work was funded by grants from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (UM1AI068635, UM1AI068614, 3UM1Al148575-01S2, and UM1AI069412). The mRNA-1273-P301 study is sponsored by Moderna, but no other funding or support was provided for this nested substudy .
Paper cited: Follmann D et al. “Antinucleocapsid Antibodies After SARS-CoV-2 Infection in the Blinded Phase of the Randomized, Placebo-Controlled mRNA-1273 COVID-19 Vaccine Efficacy Clinical Trial” Annals of Internal Medicine DOI: 10.7326/M22-1300
Annals of Internal Medicine
Meta-analysis
People
Antinucleocapsid Antibodies After SARS-CoV-2 Infection in the Blinded Phase of the Randomized, Placebo-Controlled mRNA-1273 COVID-19 Vaccine Efficacy Clinical Trial
5-Jul-2022
Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M22-1300