Oligosymptomatic long-term carriers of SARS-CoV-2 display impaired innate resistance and high Spike-specific neutralizing antibodies

The vast spectrum of clinical features of COVID-19 keeps challenging scientists and clinicians. Control of pathogen load (host resistance) and prevention of tissue damage (disease tolerance) are essential for the outcome of infectious diseases. Both low resistance and high disease tolerance might result in long-term viral persistence, but the underlying mechanisms remain unclear. Here, we studied the immune response of immunocompetent COVID-19 patients with prolonged SARS-CoV-2 infection by immunophenotyping, cytokine and serological analysis. Despite viral loads and symptoms comparable to regular mildly-symptomatic patients, long-term carriers displayed weaker systemic IFN-I responses and fewer circulating pDCs and NK cells at disease onset. Type 1 cytokines remained low, while type-3 cytokines were in turn enhanced. Interestingly, the plasma of these patients showed a higher spike-specific neutralization capacity. The identification of very early distinct immune responses in long-term carriers adds up to our understanding on essential host protective mechanisms to ensure tissue damage control despite prolonged viral infection. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by ANRS | Maladies infectieuses emergentes/INSERM grant (MUCOVID-007) (to DK and MTB); by CAPES, Edital de Selecao Emergencial II CAPES grant 88887.507381/2020-00 (to MTB); by Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ), grant E-26/201.128/2022 (272688) and E-26/211.564/2019 (252360) (to MTB), E-26/010.002434/2019 and E-26/210.178/2020 (to AT), E-26/203.002/208 (to A.M.V.); by Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) grant 312477/2021-0 (to MTB) and grants 439649/2018-8 and 316796/2021-2 (to A.M.V.); Instituto Serrapilheira (to AT). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: CONEP (National Ethics Committee for Research) and is entitled Characterization of risk factors and development of new serum tests for SARS-CoV-Infection Ethic Committee Board (CAAE: 30161620.0.1001.5257; 4.245.490) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors