3. updated statement on the immunity of convalescents

The common antigen that a person comes into contact with in both SARS-CoV-2 infection and vaccination is the SARS-CoV-2 surface protein S (also called spike protein). Antibodies against the spike protein bind to the virus and can prevent the virus from attaching to the cell. Therefore, these neutralising antibodies are the most commonly measured indicator of protection from infection. The SARS-CoV-2 variant Omikron has numerous changes (mutations) in the spike protein, so that it is able to at least partially escape the antibody response of the recovered and vaccinated. This is referred to as immune escape.

In order to have good protection against infection with this variant, a sufficiently high level of neutralizing antibodies is required. Antibodies directed against SARS-CoV-2 are formed in varying quality and quantity after vaccination or recovery, but this decreases again over time. The effectiveness of neutralizing antibodies is measured in the laboratory in specific neutralization tests. Various publications have shown that the serum of people who have not been vaccinated and have been infected with SARS-CoV-2 (not omicron) has a low, sometimes undetectable neutralizing activity against the omicron variant (e.g. Rössler et al., 2022[1]; Planas et al., 2021[2]; Hoffmann et al., 2022[3]; Carreño et al., 2021[4]). Sera from individuals who have undergone a combination of infection and vaccination, or from vaccinated individuals who have received a booster vaccination, show a better neutralizing antibody response against the Omicron variant (e.g. Rössler et al., 2022[1]; Planas et al., 2021[2]; Hoffmann et al., 2022[3]; Carreño et al., 2021[4]).

In addition to antibodies, cellular immunity also plays a role in the defense against SARS-CoV-2 infection (e.g. Moderbacher et al., 2020[5]; Tan et al., 2021[6]). Important here are so-called T cells, which recognize and destroy virus-infected cells. Protection against severe courses of COVID-19 therefore depends not only on neutralizing antibodies, but also on the ability of T cells to recognize and kill infected cells in the body. Initial publications indicate that, in contrast to the antibody response, the T-cell response remains effective in both recovered and fully vaccinated individuals when infected with the omicron variant (e.g. Keeton et al., 2022[7]; Gao et al., 2022[8]; GeurtsvanKessel et al., 2022[9]). This is due to the fact that the targets recognized by the T cells are little changed in the SARS-CoV-2 variants. It can be assumed that these T-cell responses can provide good protection against severe COVID-19 courses after infection with the omicron variant, although no data are available on this to date. In contrast, they are generally unable to protect against infection with the omicron variant due to the mode of action of T cells.

The Robert Koch Institute (RKI) announced on its homepage on 15.01.2022 that the duration of the recovery status will be reduced from 6 months to 90 days in future. An updated version[10] of the RKI website refers to the following: "These technical requirements for proof of recovery refer exclusively to persons who are unvaccinated, i.e. who have not received a vaccination either before or after their infection." It is also pointed out that these guidelines are subject to change in line with the latest scientific findings.

However, in the implementation of this rule change, a distinction was often not made between convalescents without or with vaccination. In the opinion of Society of Virology , however, a clear distinction must be made between:

1. convalescents without COVID-19 vaccination history

These are convalescents who have not received a vaccination at any time.

2. convalescents with COVID-19 vaccination history

These are convalescents with a history of COVID-19 vaccination in various combinations in addition to infection.

The latest publications (Wratil et al., 2022[11]; Walls et al., 2022[12]; Gruell et al., 2022[13]) show that, due to the booster effect, SARS-CoV-2-specific antibodies with a high neutralization capacity and in sufficient quantities develop after several antigen contacts over time. The number of antigen contacts is decisive here, whereby an antigen contact is either a single vaccination (i.e. one vaccination dose) or an infection. For example, a fully vaccinated person (i.e. after two vaccine doses) who has also had an infection has a total of three antigen contacts. The studies show that after three antigen contacts, high-quality antibodies against the SARS-CoV-2 virus develop, which are also able to at least partially neutralize the omicron variant. This is independent of the different constellations of antigen contacts, i.e. regardless of whether a person is triple-vaccinated, double-vaccinated and recovered or recovered and double-vaccinated.

However, there must be an interval of several weeks between two antigen contacts. For example, recovered patients who receive two vaccinations only 3 weeks apart do not show an increase in antibody response after the second vaccination compared to the first vaccination (Wratil et al., 2022[11]). At present, it is not possible to say how long protection lasts for people with multiple infections without vaccination. In addition, it is currently unclear how long and to what extent protection persists in recovered individuals with only one vaccination (2 antigen contacts).

There is also no data available for other conceivable combinations of the composition of the 3 antigen contacts. However, it can be assumed that high-quality antibodies against SARS-CoV-2 will also be developed in these cases. However, the available data show that convalescents (not Omikron) without prior or subsequent vaccination develop only a low, sometimes undetectable antibody response against the Omikron variant (e.g. Rössler et al, 2022; Planas et al., 2021; Hoffmann et al., 2022; Carreño et al., 2021)[1-4] and protection against infection with the omicron variant is also significantly reduced compared to infection with the delta variant (Andeweg et al., 2022[14]). For this reason, at least one booster vaccination is recommended for these people.

Taking this data situation into account (as of 10.02.2022), Society of Virology proposes applying a pragmatic regulation throughout Germany that equates people with three antigen contacts, regardless of the type of antigen contact (vaccination or infection). This is already the case in some federal states, e.g. in Hamburg[15] and Bavaria[16], where this group of people (3 antigen contacts) is largely exempt from testing when applying the 2Gplus rule. This procedure means that people who have only recovered or have only been vaccinated twice cannot be treated in the same way as people with three antigen contacts.

If the data situation changes and new information is added, which is to be assumed, this statement will be adapted again.

The Board of Directors of the Society of Virology

Prof. Dr. Ralf Bartenschlager, Heidelberg University Hospital

Prof. Dr. Thomas Stamminger, University Hospital Ulm

Prof. Dr. Ulf Dittmer, University Hospital Essen

Prof. Dr. Sandra Ciesek, University Hospital Frankfurt

Prof. Dr. Klaus Überla, Erlangen University Hospital

With the participation of

Prof. Dr. Hartmut Hengel, University Hospital Freiburg

PD Dr Hanna-Mari Baldauf, LMU Munich

[1] Rössler A, Riepler L, Bante D, von Laer D, Kimpel J. SARS-CoV-2 Omicron Variant Neutralization in Serum from Vaccinated and Convalescent Persons. N Engl J Med. 2022 Jan 12:NEJMc2119236. doi: 10.1056/NEJMc2119236. Epub ahead of print. PMID: 35021005; PMCID: PMC8781314.

[2] Planas D, Saunders N, Maes P, Guivel-Benhassine F, Planchais C, Buchrieser J, Bolland WH, Porrot F, Staropoli I, Lemoine F, Péré H, Veyer D, Puech J, Rodary J, Baele G, Dellicour S, Raymenants J, Gorissen S, Geenen C, Vanmechelen B, Wawina-Bokalanga T, Martí-Carreras J, Cuypers L, Sève A, Hocqueloux L, Prazuck T, Rey F, Simon-Loriere E, Bruel T, Mouquet H, André E, Schwartz O. Considerable escape of SARS-CoV-2 Omicron to antibody neutralization. Nature. 2021 Dec 23. doi: 10.1038/s41586-021-04389-z. Epub ahead of print. PMID: 35016199.

[3] Hoffmann M, Krüger N, Schulz S, Cossmann A, Rocha C, Kempf A, Nehlmeier I, Graichen L, Moldenhauer AS, Winkler MS, Lier M, Dopfer-Jablonka A, Jäck HM, Behrens GMN, Pöhlmann S. The Omicron variant is highly resistant against antibody-mediated neutralization: Implications for control of the COVID-19 pandemic. Cell. 2022 Feb 3;185(3):447-456.e11. doi: 10.1016/j.cell.2021.12.032. Epub 2021 Dec 24. PMID: 35026151; PMCID: PMC8702401.

[4] Carreño JM, Alshammary H, Tcheou J, Singh G, Raskin A, Kawabata H, Sominsky L, Clark J, Adelsberg DC, Bielak D, Gonzalez-Reiche AS, Dambrauskas N, Vigdorovich V; PSP/PARIS Study Group, Srivastava K, Sather DN, Sordillo EM, Bajic G, van Bakel H, Simon V, Krammer F. Activity of convalescent and vaccine serum against SARS-CoV-2 Omicron. Nature. 2021 Dec 31. doi: 10.1038/s41586-022-04399-5. Epub ahead of print. PMID: 35016197.

[5] Rydyznski Moderbacher C, Ramirez SI, Dan JM, Grifoni A, Hastie KM, Weiskopf D, Belanger S, Abbott RK, Kim C, Choi J, Kato Y, Crotty EG, Kim C, Rawlings SA, Mateus J, Tse LPV, Frazier A, Baric R, Peters B, Greenbaum J, Ollmann Saphire E, Smith DM, Sette A, Crotty S. Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity. Cell. 2020 Nov 12;183(4):996-1012.e19. doi: 10.1016/j.cell.2020.09.038. Epub 2020 Sep 16. PMID: 33010815; PMCID: PMC7494270.

[6] Tan AT, Linster M, Tan CW, Le Bert N, Chia WN, Kunasegaran K, Zhuang Y, Tham CYL, Chia A, Smith GJD, Young B, Kalimuddin S, Low JGH, Lye D, Wang LF, Bertoletti A. Early induction of functional SARS-CoV-2-specific T cells associates with rapid viral clearance and mild disease in COVID-19 patients. Cell Rep. 2021 Feb 9;34(6):108728. doi: 10.1016/j.celrep.2021.108728. Epub 2021 Jan 21. PMID: 33516277

[7] Keeton R, Tincho MB, Ngomti A, Baguma R, Benede N, Suzuki A, Khan K, Cele S, Bernstein M, Karim F, Madzorera SV, Moyo-Gwete T, Mennen M, Skelem S, Adriaanse M, Mutithu D, Aremu O, Stek C, du Bruyn E, Van Der Mescht MA, de Beer Z, de Villiers TR, Bodenstein A, van den Berg G, Mendes A, Strydom A, Venter M, Giandhari J, Naidoo Y, Pillay S, Tegally H, Grifoni A, Weiskopf D, Sette A, Wilkinson RJ, de Oliveira T, Bekker LG, Gray G, Ueckermann V, Rossouw T, Boswell MT, Bihman J, Moore PL, Sigal A, Ntusi NAB, Burgers WA, Riou C. T cell responses to SARS-CoV-2 spike cross-recognize Omicron. Nature. 2022 Jan 31. doi: 10.1038/s41586-022-04460-3. Epub ahead of print. PMID: 35102311.

[8] Gao Y, Cai C, Grifoni A, Müller TR, Niessl J, Olofsson A, Humbert M, Hansson L, Österborg A, Bergman P, Chen P, Olsson A, Sandberg JK, Weiskopf D, Price DA, Ljunggren HG, Karlsson AC, Sette A, Aleman S, Buggert M. Ancestral SARS-CoV-2-specific T cells cross-recognize the Omicron variant. Nat Med. 2022 Jan 14. doi: 10.1038/s41591-022-01700-x. Epub ahead of print. PMID: 35042228.

[9] GeurtsvanKessel CH, Geers D, Schmitz KS, Mykytyn AZ, Lamers MM, Bogers S, Scherbeijn S, Gommers L, Sablerolles RSG, Nieuwkoop NN, Rijsbergen LC, van Dijk LLA, de Wilde J, Alblas K, Breugem TI, Rijnders BJA, de Jager H, Weiskopf D, van der Kuy PHM, Sette A, Koopmans MPG, Grifoni A, Haagmans BL, de Vries RD. Divergent SARS CoV-2 Omicron-reactive T- and B cell responses in COVID-19 vaccine recipients. Sci Immunol. 2022 Feb 3:eabo2202. doi: 10.1126/sciimmunol.abo2202. Epub ahead of print. PMID: 35113647.

[10] https://www.rki.de/DE/Content/InfAZ/N/Neuartiges_Coronavirus/Genesenennachweis.html (as at 08.02.2022)

[11] Wratil PR, Stern M, Priller A, Willmann A, Almanzar G, Vogel E, Feuerherd M, Cheng CC, Yazici S, Christa C, Jeske S, Lupoli G, Vogt T, Albanese M, Mejías-Pérez E, Bauernfried S, Graf N, Mijocevic H, Vu M, Tinnefeld K, Wettengel J, Hoffmann D, Muenchhoff M, Daechert C, Mairhofer H, Krebs S, Fingerle V, Graf A, Steininger P, Blum H, Hornung V, Liebl B, Überla K, Prelog M, Knolle P, Keppler OT, Protzer U. Three exposures to the spike protein of SARS-CoV-2 by either infection or vaccination elicit superior neutralizing immunity to all variants of concern. Nat Med. 2022 Jan 28. doi: 10.1038/s41591-022-01715-4. Epub ahead of print. PMID: 35090165.

[12] Walls AC, Sprouse KR, Bowen JE, Joshi A, Franko N, Navarro MJ, Stewart C, Cameroni E, McCallum M, Goecker EA, Degli-Angeli EJ, Logue J, Greninger A, Corti D, Chu HY, Veesler D. SARS-CoV-2 breakthrough infections elicit potent, broad, and durable neutralizing antibody responses. Cell. 2022 Jan 20:S0092-8674(22)00069-1. doi: 10.1016/j.cell.2022.01.011. Epub ahead of print. PMID: 35123650.

[13] Gruell H, Vanshylla K, Tober-Lau P, Hillus D, Schommers P, Lehmann C, Kurth F, Sander LE, Klein F. mRNA booster immunization elicits potent neutralizing serum activity against the SARS-CoV-2 Omicron variant. Nat Med. 2022 Jan 19:1-4. doi: 10.1038/s41591-021-01676-0. Epub ahead of print. PMID: 35046572; PMCID: PMC8767537.

[14] AndewegSP, de Gier B, Eggink D, van den Ende D, van Maarseveen N, Ali L, Vlaemynck B, Schepers R, RIVM COVID-19 surveillance and epidemiology team, Hahné SJM, Reusken C, de Melker fHE, van den Hof S, Knol MJ. Protection of COVID-19 vaccination and previous infection against Omicron BA.1 and Delta SARS-CoV-2 infections, the Netherlands, 22 November 2021- 19 January 2022. https://doi.org/10.1101/2022.02.06.22270457doi: medRxiv preprint

[15] https://www.hamburg.de/corona-schutzimpfung/15781988/quarantae-isolation-test (as at 12.02.2022)

[16] https://www.buergerbeauftragter.bayern/corona-aktuell (as at 09.02.2022)