SARS-CoV-2 Exposure Can Trigger MERS-Reactive Antibodies Without True MERS Infection
Serologic testing for MERS-CoV has taken on new complexity in the COVID-19 era. In serum samples from people in the Netherlands with prior SARS-CoV-2 exposure, antibodies that bound MERS-CoV were common, and in a subset of patients with severe COVID-19, those antibodies even showed neutralizing activity against MERS-CoV. The biologic explanation is straightforward: the spike proteins of SARS-CoV-2 and MERS-CoV share conserved regions, especially in the S2 domain, and the immune system can generate antibodies that recognize those shared structures even without any MERS infection history.
The practical consequence reaches beyond laboratory curiosity. A positive MERS serology result can be used to identify past infection during outbreaks or in surveillance settings where molecular testing is absent or incomplete. When SARS-CoV-2-induced antibodies imitate that signal, the risk of misclassifying prior MERS exposure rises immediately.
Severe COVID-19 Produced the Strongest MERS Cross-Reactivity
The study compared serum from three SARS-CoV-2 exposure groups: persons with mild COVID-19, persons with severe COVID-19 admitted to the intensive care unit, and people who had received multiple COVID-19 vaccinations, many of whom also had breakthrough infection. Sampling windows differed across groups, with collection occurring 28 days after vaccination, 59 days after symptom onset in mild illness, and 1 day after intensive care admission in severe illness. Because the cohorts were assembled in the Netherlands, prior MERS-CoV exposure was assumed to be absent.
Across the SARS-CoV-2–exposed groups, binding antibody patterns against SARS-CoV-2 spike, S1, and S2 were broadly similar, but the magnitude was highest in vaccinated participants, followed by those with severe infection and then mild infection. Neutralizing titers against SARS-CoV-2 followed the same general hierarchy. This part of the dataset matters because it establishes that the same sera capable of robust SARS-CoV-2 responses were also the ones most likely to show MERS cross-reactivity.
The MERS-CoV findings were more selective. All SARS-CoV-2-exposed groups contained sera that bound MERS-CoV full spike, but the strongest binding appeared after severe COVID-19, with median levels of 7.1 IU/mL compared with 1.8 IU/mL after vaccination and 1.1 IU/mL after mild infection. Cross-reactivity concentrated in the S2 domain. Median MERS-CoV S2 binding reached 67.0 IU/mL in the severe COVID-19 group, versus 21.0 IU/mL in mild infection and 17.1 IU/mL in vaccinated persons. Even prepandemic sera showed some S2 binding, suggesting background reactivity with related coronaviruses already circulating in humans.
Severe infection did more than raise binding signals. A subset of 11 patients with severe COVID-19 had antibodies capable of neutralizing MERS-CoV, and one serum sample from the mild COVID-19 group partially neutralized MERS-CoV as well. Neutralizing titers ranged from 26 to 694. Vaccinated participants, despite multiple SARS-CoV-2 exposures, did not show the same neutralizing pattern against MERS-CoV.
Full-Spike Assays Risk False Positives, While S1 Tightens Specificity
The central laboratory question was whether the WHO-recommended two-step MERS serology strategy still holds in the presence of SARS-CoV-2 immunity. Investigators examined the relationship between MERS-CoV neutralization and antibody binding. In severe COVID-19 samples, neutralizing activity correlated with binding to MERS-CoV full spike, and some sera were double-positive on both measures. The correlation was driven largely by S2 binding, which is exactly where the structural similarity between these viruses is greatest.
That pattern creates a problem for assays built around full spike or S2 alone. They are vulnerable to cross-reactive signals from SARS-CoV-2 exposure, and the resulting serologic profile can resemble prior MERS infection even when none has occurred.
S1 behaved differently. MERS-CoV S1 binding was low, showed no correlation with neutralization, and produced only one double-positive sample across the SARS-CoV-2–exposed cohorts. In other words, combining MERS-CoV S1 binding with a neutralization assay sharply reduced the influence of SARS-CoV-2-induced cross-reactivity. A commercial MERS-CoV S1 ELISA was even more specific than the in-house assay used in the study, although it appeared less sensitive. Every sample that was positive by the in-house method and capable of neutralization still remained below the positivity cutoff in the commercial S1 assay.
The biology fits the assay behavior. S1 contains more distinct antigenic regions than S2, so it better separates true MERS exposure from antibodies raised against SARS-CoV-2. The cost of raising the cutoff, however, is lower sensitivity, which means some genuine low-level MERS antibody responses could be missed. Laboratory specificity and clinical sensitivity continue to pull in opposite directions.
Serology Strategy After the Pandemic Needs a Narrower Antigen Target
These findings directly affect how MERS surveillance should be interpreted now that SARS-CoV-2 exposure is nearly universal in many populations. Vaccination and infection can both generate antibodies that bind MERS-CoV, especially in assays that rely on the full spike protein or S2. Severe COVID-19 appears most capable of driving the kind of cross-reactive response that can blur the line between prior SARS-CoV-2 and prior MERS-CoV exposure.
For diagnostic laboratories, the safer path is a serologic algorithm built around MERS-CoV S1 binding plus neutralization, rather than full-spike or S2-centered screening alone. That approach preserves specificity better in a population already shaped by SARS-CoV-2 immunity. It also reduces the chance that public health surveillance will overestimate MERS seroprevalence.
The study also points to a mechanistic difference between natural infection and vaccination. Severe COVID-19 may expose the immune system to larger antigen loads and to spike conformations different from the prefusion-stabilized spikes used in vaccines, increasing the likelihood of antibodies against conserved S2 epitopes. Vaccination, despite producing strong SARS-CoV-2 binding and neutralizing responses, did not generate the same pattern of MERS neutralization in this cohort.
MERS serology now has to be read against the immune background left by SARS-CoV-2. The assay choice, not just the antibody result, determines whether past MERS infection is genuinely being detected or simply mimicked by cross-reactive coronavirus immunity.