Shedding light on the number of undetected SARS-CoV-2 infections

Nationwide antibody study “MuSPAD”of the HZI investigated the differences of the first three pandemic waves in seven regions of Germany

Between July 2020 and August 2021, the Epidemiology Department of the Helmholtz Centre for Infection Research (HZI) in Braunschweig examined the blood of approximately 26,000 individuals for antibodies against the SARS-CoV-2 coronavirus as part of the nationwide “MuSPAD” study. For samples collected between July and October 2020, it became evident that one to three per cent of the people had experienced a SARS-CoV-2 infection after the first wave. By the end of the third wave, the seroprevalence had increased but remained at less than 15 per cent at most study sites. Therefore, while there were two to five actual infections for every reported infection during the first wave, this ratio - and thus the number of undetected cases - decreased in the second and third waves. These results were recently published in the international issue of Deutsches Ärzteblatt. In addition, a preprint publication of another study investigating the immune response after vaccination against SARS-CoV-2 based on samples from the MuSPAD study is under review.

Eine Vielzahl blauer und wenige rote Spielfiguren.© Adobe Stock / Paulista  Even though many infections with SARS-CoV-2 cause only mild cold symptoms or are asymptomatic, the high total number of infections necessitates effective protective measures to protect the most vulnerable groups from severe courses of the disease. To this end, it is important to be able to estimate the number of undetected infections. It is also particularly interesting to find out, in which areas of life the majority of infections occur and how many people, on average, have the virus transmitted to them by each infected person. Consequently, in July 2020, the Helmholtz Centre for Infection Research (HZI) launched the “Multilocal and Serial Prevalence Study on Antibodies to SARS-CoV-2 Coronavirus in Germany” (MuSPAD) under the supervision of Prof Gérard Krause, who heads the Department of Epidemiology at the HZI. The scientists used blood samples to determine the antibody status in the population of seven counties that were affected to varying degrees by the pandemic.

Reutlingen, Freiburg, Aachen, Osnabrück, Magdeburg, Chemnitz and Vorpommern-Greifswald were selected as the study sites. The first six of these counties were sampled twice, three to four months apart. Nearly 17,000 donors ranging in age from 18 to 99 participated in the first round. In the second round, nearly 40 per cent of these donors participated again, while more than 9,000 unvaccinated donors were newly added at six study sites. To ensure a representative cross-section of the population, invitations were sent to addresses obtained randomly from the respective population registration offices. Study participants donated nine millilitres of blood and answered several questionnaires about their living conditions and health status.

“Due to the size of the study, its geographic distribution and the multi-step examinations, this study allows us to identify specific peculiarities and take them into account in the evaluation,” says Gérard Krause. “This allows us to better assess the pandemic process and the effectiveness of protective measures in different regions and population groups in Germany.”

Up to October 2020, the seroprevalence weighted by age and gender (the proportion of study participants with antibodies in their blood), ranged from 1.3 to 2.6 per cent (samples collected in Freiburg, Reutlingen, Aachen and Osnabrück). “During this period, the majority of the reported cases were infections during the first wave. Since the intensity of testing was still low and many infections remain asymptomatic in spring and summer, we recorded strong under-reporting by a factor of three to five,” says Dr Berit Lange, Head of Clinical Epidemiology at the HZI. For the study sites sampled only after the second or third wave through August 2021, an additional 2.4 to 19.9 per cent of the unvaccinated population had experienced infection. The rate of undetected cases was lower at most sites during the second and third waves as compared to the first wave.

Additionally, the researchers found that 14 per cent of study participants who were quarantined as contacts of an infected individual, had indeed been exposed to the virus as shown by the presence of antibodies. A total of 2.1 per cent of the study participants, who had never been quarantined, had antibodies to SARS-CoV-2 in their blood.

The results from Chemnitz, the final study site from July 2021 were quite different. In Chemnitz, the weighted seroprevalence among subjects who had not yet been vaccinated was 32.4 per cent. “This strong increase compared to the first examination in March (13.1 per cent) may be explained by more people with known SARS-CoV-2 infection agreeing to participate when they were invited. In addition, a larger proportion of the unvaccinated, compared to vaccinated people, may have already experienced infection,” Lange says.

In conclusion, MuSPAD demonstrated that even after the third wave, the majority of the unvaccinated population has not yet developed immunity to the virus. The number of undetected cases was lower in the second and third waves than in the first. On average, one in seven people ordered to quarantine had indeed become infected.

“Although the study could unfortunately not be extended in order to appropriately investigate current and future waves as well, this study is already contributing to the current assessment of the situation,” says Gérard Krause. “In further analyses, we aim to pursue immunological and societal issues in more detail.”

In another study in cooperation with the Natural and Medical Sciences Institute in Reutlingen, the immune response after SARS-CoV-2 vaccination was investigated using samples from the MuSPAD study. Two specifically developed multiplex tests were used. While MULTICOV-AB was used to determine the quantity of SARS-CoV-2 antibodies, RBDCoV-ACE2 analyses inhibition of binding to ACE2, determining the neutralisation strength of the antibodies present. The results show that within the general population, mRNA-based vaccines (e.g. Moderna or BioNTech), either as two doses or mixed with a vector-based vaccine from AstraZeneca, generate more antibodies with greater neutralisation potency against different SARS-CoV-2 virus variants, than vaccination with vector-based vaccines alone.

The MuSPAD study was fully funded by the Helmholtz Association of German Research Centres.

Original publication:

Gornyk D, Harries M, Glöckner S, Strengert M, Kerrinnes T, Heise JK, Maaß H, Ortmann J, Kessel B, Kemmling Y, Lange B, Krause G, on behalf of the MuSPAD Team: SARS-CoV-2 seroprevalence in Germany—a population-based sequential study in seven regions. Dtsch Arztebl Int 2021; 118. DOI: 10.3238/arztebl.m2021.0364 (online first) https://www.aerzteblatt.de/archiv/221932

Moreover, the following publication has entered the peer-review process (preprint): 

Alex Dulovic, Barbora Kessel, Manuela Harries, Matthias Becker, Julia Ortmann, Johanna Griesbaum, Jennifer Juengling, Daniel Junker, Pilar Hernandez, Daniela Gornyk, Stephan Gloeckner, Vanessa Melhorn, Stefanie Castell, Jana-Kristin Heise, Yvonne Kemmling, Torsten Tonn, Kerstin Frank, Thomas Illig, Norman Klopp, Neha Warikoo, Angelika Rath, Christina Suckel, Anne Ulrike Marzian, Nicole Grupe, Philipp D. Kaiser, Bjoern Traenkle, Ulrich Rothbauer, Tobias Kerrinnes, Gerard Krause, Berit Lange, Nicole Schneiderhan-Marra, Monika Strengert: Comparative magnitude and persistence of SARS-CoV-2 vaccination responses on a population level in Germany. medRxiv 2021; DOI: 10.1101/2021.12.01.21266960

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