SARS-CoV-2 Exposure Produced MERS-CoV Cross-Reactive Antibodies in Dutch Cohort
Serologic testing for MERS-CoV now has a more complicated backdrop. In serum samples from people in the Netherlands with prior SARS-CoV-2 exposure, antibody responses often bound MERS-CoV spike protein, and a subset of samples from severe COVID-19 even neutralized MERS-CoV in vitro. The finding matters because MERS surveillance depends heavily on serology in settings where molecular testing is absent or incomplete, yet cross-reactive antibodies from COVID-19 can make past MERS infection look more common than it truly is.
The biologic explanation sits in the spike protein itself. SARS-CoV-2 and MERS-CoV share enough structural similarity, especially in the conserved S2 domain, to permit antibody cross-binding after infection or vaccination. Even so, not all cross-reactive signals behave the same way. Binding to full spike or S2 appeared much more likely than binding to S1, and the functional neutralization signal was concentrated in the group with severe COVID-19 rather than in vaccinated participants with repeated antigen exposure.
Severe COVID-19 Drove the Strongest Cross-Reactive Signal
Investigators examined serum from three exposure groups: mild symptomatic COVID-19 before vaccines were available, severe COVID-19 requiring intensive care, and people who had received multiple COVID-19 vaccines, most of whom also had breakthrough infection. The sampling windows were different across cohorts: 59 days after symptom onset in the mild COVID-19 group, 1 day after intensive care admission in the severe group, and 28 days after vaccination in the vaccinated group. Those timing differences are not trivial. Antibody magnitude and maturation evolve quickly after infection or vaccination, and the severe group was sampled at a point when high antigen burden and acute immune activation could still be shaping the response.
SARS-CoV-2 binding IgG tracked as expected. The vaccinated group showed the highest levels of binding antibodies to full spike, S1, and S2, followed by the severe COVID-19 group and then the mild COVID-19 group. Neutralizing titers against SARS-CoV-2 were also highest among vaccinated persons. Yet the MERS-CoV profile did not mirror the SARS-CoV-2 profile. Instead, all SARS-CoV-2-exposed groups included serum capable of binding MERS-CoV full spike, with the strongest median signal in severe COVID-19, where the median was 7.1 IU/mL, compared with 1.8 IU/mL after vaccination and 1.1 IU/mL after mild infection.
One sentence captures the clinical risk: SARS-CoV-2 immunity can masquerade as MERS immunity.
Cross-reactivity was driven mainly by S2 binding. In the severe COVID-19 group, the median MERS-CoV S2 binding level reached 67.0 IU/mL, compared with 21.0 IU/mL in mild COVID-19 and 17.1 IU/mL in vaccinated participants. Even prepandemic serum showed low-level S2 binding, a reminder that seasonal coronaviruses may contribute background reactivity. Occasional S1 binding appeared as well, but it was far less common and less tightly linked to neutralizing activity.
Neutralization Confirmed the Specificity Problem
The most consequential result came from the neutralization assays. Eleven samples from the severe COVID-19 group neutralized MERS-CoV, and one sample from the mild COVID-19 group partially neutralized MERS-CoV. Neutralizing titers ranged from 26 to 694. Among the severe COVID-19 samples, MERS-CoV neutralization correlated with full-spike binding, and those double-positive samples were also the ones most likely to show S2-driven binding. In other words, the assay pattern itself pointed to broad conserved-spike recognition rather than true MERS exposure.
The WHO laboratory approach recommends a positive screening assay followed by neutralization to support evidence of past MERS infection. These data sharpen that guidance. If the screening assay relies on full spike or S2, SARS-CoV-2-induced antibodies can generate false-positive MERS patterns. S1 performed better. MERS-CoV S1 binding did not correlate with neutralization, and only one sample from the SARS-CoV-2-exposed cohorts was double-positive when S1 binding was paired with neutralization, which suggests a far lower risk of misclassification than with full-spike or S2-based testing.
What the Assay Choice Means for Surveillance
The practical consequence reaches beyond the laboratory bench. MERS serosurveillance is used to estimate how often human infections occur, to investigate outbreaks, and to define risk in populations with camel exposure or healthcare-linked contact. If SARS-CoV-2 exposure inflates apparent MERS seropositivity, public health programs could overestimate transmission and misread the geographic footprint of MERS-CoV. That would be especially problematic in regions where MERS is monitored infrequently and where every serologic signal carries weight.
The commercial MERS-CoV S1 ELISA in this study did not return positive results in samples that were positive by the in-house ELISA and capable of MERS-CoV neutralization. The commercial assay therefore appeared more specific, though less sensitive, than the in-house test. A stricter cutoff can protect specificity, but it can also miss low-level true positives. The tradeoff is familiar in infectious disease serology: tightening the net reduces false positives, but it can also drop real infections that sit near the threshold.
The nucleocapsid protein offers no easy escape. Because SARS-CoV-2 infection can also induce antibodies that bind MERS-CoV nucleocapsid, that antigen is a poor choice for clean discrimination between the two viruses. The field therefore needs a strategy that reduces cross-reactivity without erasing sensitivity altogether.
Severe Infection, Not Vaccination, Appeared to Favor Functional Cross-Reactivity
A striking feature of the dataset is the difference between severe infection and vaccination. Repeated vaccination produced strong SARS-CoV-2 binding and neutralization, yet did not generate detectable MERS-CoV neutralizing antibodies in the same way severe COVID-19 did. The likely reason lies in the antigenic context. Severe infection may expose the immune system to larger amounts of viral protein and different spike conformations than prefusion-stabilized vaccine antigen, increasing the chance of antibodies against conserved S2 epitopes. Those epitopes are shared across coronaviruses, which explains why severe infection can leave behind a broader, less species-specific antibody footprint.
For diagnostic laboratories, the message is direct: combine MERS-CoV S1 binding with neutralization when looking for past infection, and avoid interpreting full-spike or S2 signals in isolation. The study did not include proven MERS cases for direct comparison, and the cohorts were all from the Netherlands, where MERS exposure was assumed absent. Even so, the data provide a clear warning for serologic interpretation in the post-COVID era. Cross-reactive antibodies are common, and some of them are not just binding curiosities; they can neutralize.