COVID-19 mRNA Vaccines may Cause False Reactivity in Some Serologic Laboratory Tests, Including Rapid Plasma Reagin Tests

Dimitrios Korentzelos, MD; Vandana Baloda, MD; Yujung Jung, MD; Bradley Wheeler; Michael R. Shurin, MD, PhD; Sarah E. Wheeler, PhD


Am J Clin Pathol. 2022;158(2):162-166. 

In This Article

Abstract and Introduction


Objectives: Acute viral infections and some vaccines have been shown to increase false positivity in serologic assays. We assessed if the messenger RNA coronavirus disease 2019 (COVID-19) vaccines could cause false reactivity in common serologic assays in a pilot longitudinal cohort.

Methods: Thirty-eight participants with sera available prevaccination, 2 weeks after each vaccine dose, and monthly thereafter for up to 5 months were tested for common infectious disease serologies and antiphospholipid syndrome (APS) serology markers on the BioPlex 2200, Sure-Vue rapid plasma reagin (RPR), and Macro-Vue RPR. Twenty-two participants received the Moderna vaccine and 16 received the Pfizer vaccine.

Results: Most assays had no change in reactivity over the course of the sample draws, including APS markers. Epstein-Barr virus immunoglobulin G (IgG), measles IgG, and rubella immunoglobulin M all had possible false reactivity in one to two participants. RPR tests demonstrated false reactivity, with baseline nonreactive participant samples becoming reactive following vaccination. There were more false reactive participants (7/38) in the BioPlex RPR than in the Sure-Vue (2/38) and Macro-Vue (1/38) tests. All falsely reactive RPR tests were in participants who received the Moderna vaccine.

Conclusions: Serologic assays with results that do not fit the clinical picture following COVID-19 vaccination should be repeated. Effects of false reactivity can last more than 5 months in some assays. In particular, RPR is susceptible to false reactivity, and there is variability among assays. Larger longitudinal studies are needed to determine the incidence and window of false reactivity.


The introduction of vaccines to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a turning point in the coronavirus disease 2019 (COVID-19) pandemic, with the largest known scale of vaccine creation and distribution in history.[1] Immune responses created to vaccination with messenger RNA (mRNA) SARS-CoV-2 vaccines include B- and T-cell–specific responses to the mRNA aided by lipid nanoparticles functioning as adjuvants.[2] In addition, work on previous vaccines has demonstrated that transient interference in serologic assays after vaccination may occur.[3] Specifically, following smallpox vaccination, several studies since the 1940s have found biologically false-positive serologic results in nontreponemal tests.[4–7] Acute viral infections such as hepatitis C virus, Epstein-Barr virus (EBV), cytomegalovirus (CMV), hepatitis B virus, and SARS-CoV-2 have been implicated in falsely reactive serologies for a host of infectious disease (ID) and autoimmune markers.[8–10] We sought to determine if SARS-CoV-2 vaccination could cause false reactivity in standard ID assays.