{"doi":"10.1016/j.ymthe.2020.10.003","title":"The Road Less Traveled: SARS-CoV-2 and Cell-Mediated Immunity","abstract":"When it comes to SARS-CoV-2 (severe acute respiratory syndrome-associated coronavirus 2), the dominant narrative seems to be all about antibodies to achieve sterile immunity. If it is not one of a myriad of vaccine candidates and their purported protective antibody titers, then it is convalescent antibodies or perhaps one of the several new broadly neutralizing antibody approaches to treat CoV-2 infection. It is impressive how much money and effort is ongoing in the development of antibodies to deal with CoV-2 despite studies from several decades ago indicating that, while protection from coronavirus infection is achievable with antibodies, these antibodies cannot eradicate ongoing infection and therefore most likely have little therapeutic impact.1Pope M. Chung S.W. Mosmann T. Leibowitz J.L. Gorczynski R.M. Levy G.A. Resistance of naive mice to murine hepatitis virus strain 3 requires development of a Th1, but not a Th2, response, whereas pre-existing antibody partially protects against primary infection.J. Immunol. 1996; 156: 3342-3349PubMed Google Scholar Why then, would we spend so much effort on convalescent antibody approaches, for instance? It is not even clear that convalescent antibodies are effective and, even if a modest fraction of these antibodies were found to have some efficacy against the virus or coronavirus disease 2019 (COVID-19), how would such an approach be scaled up and distributed or even experimentally vetted without proper controlled studies and a standardized therapeutic? What does appear important, based on previous coronavirus studies, is that antibody responses are only protective if they are expressed at the time of infection.1Pope M. Chung S.W. Mosmann T. Leibowitz J.L. Gorczynski R.M. Levy G.A. Resistance of naive mice to murine hepatitis virus strain 3 requires development of a Th1, but not a Th2, response, whereas pre-existing antibody partially protects against primary infection.J. Immunol. 1996; 156: 3342-3349PubMed Google Scholar But is it even possible to achieve stable protective antibody concentrations at the time of infection in humans through vaccination? In ongoing studies, only ∼4%–6% of Swedes sampled have antibodies to CoV-2. Surely more than 6% of the Swedish population must have been exposed to CoV-2 and may, in fact, have some level of immunity. More interesting are observations that antibodies to CoV-2 wane quickly in individuals who have recovered from COVID-19,2Ibarrondo F.J. Fulcher J.A. Goodman-Meza D. Elliott J. Hofmann C. Hausner M.A. Ferbas K.G. Tobin N.H. Aldrovandi G.M. Yang O.O. Rapid Decay of Anti-SARS-CoV-2 Antibodies in Persons with Mild Covid-19.N. Engl. J. Med. 2020; 383: 1085-1087Crossref PubMed Scopus (742) Google Scholar while, to date, only a few individuals have become re-infected with CoV-2.3To K.K. Hung I.F. Ip J.D. Chu A.W. Chan W.M. Tam A.R. Fong C.H. Yuan S. Tsoi H.W. Ng A.C. et al.COVID-19 re-infection by a phylogenetically distinct SARS-coronavirus-2 strain confirmed by whole genome sequencing.Clin. Infect. Dis. 2020; (Published online August 25, 2020)https://doi.org/10.1093/cid/ciaa1275Crossref Scopus (403) Google Scholar So what drives immunity to CoV-2 if not antibodies and the humoral response? There seem to be signs in the literature that cell-mediated immunity may play a large and underappreciated role and that antibodies, and in general the T helper cell type 2 (Th2) humoral immune response, comprise only a small part of host responses to coronaviruses. Have we missed the forest for the trees? Early studies noted distinct differences in the Th1 response to SARS-CoV-1 infection, which, similar to CoV-2, also results in acute respiratory distress syndromes (ARDSs). Most notable are the differences observed between young and old mice exposed to virus, with the older infected mice succumbing to ARDS within the first week following infection while younger mice remain largely resistant to the infection.4Nagata N. Iwata N. Hasegawa H. Fukushi S. Hara","journal":"Molecular Therapy","year":2020,"id":118158,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.959,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":382492,"name":"Kevin V. 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