{"doi":"10.1016/j.ymthe.2020.06.005","title":"The Improbability of the Rapid Development of a Vaccine for SARS-CoV-2","abstract":"The coronavirus SARS-CoV-2 (Cov-2) has emerged on the world stage as a pandemic. It is a highly infectious agent that can spread rapidly and has a mortality rate of ∼2%–5%. Similar to its cousin, SARS-CoV-1 (Cov-1), CoV-2 employs the angiotensin converting enzyme 2 (ACE2) receptor and the serine protease TMPRSS2 to infect lung epithelial cells. CoV-2 also infects lung endothelial cells and macrophages and monocytes.1Li H. Liu L. Zhang D. Xu J. Dai H. Tang N. Su X. Cao B. SARS-CoV-2 and viral sepsis: observations and hypotheses.Lancet. 2020; 395: 1517-1520Abstract Full Text Full Text PDF PubMed Scopus (852) Google Scholar Intriguingly, macrophages do not express appreciable levels of ACE2 or TMPRSS2,1Li H. Liu L. Zhang D. Xu J. Dai H. Tang N. Su X. Cao B. SARS-CoV-2 and viral sepsis: observations and hypotheses.Lancet. 2020; 395: 1517-1520Abstract Full Text Full Text PDF PubMed Scopus (852) Google Scholar suggesting that this virus might use an entirely different receptor and a serine protease other than TMPRSS2 to infect these immune cells. An alternative, and possibly more likely explanation, based on a plethora of past studies with other coronaviruses, is that Cov-2 employs antibody-dependent enhancement (ADE) to infect immune cells.2Pedersen N.C. An update on feline infectious peritonitis: virology and immunopathogenesis.Vet. J. 2014; 201: 123-132Crossref PubMed Scopus (150) Google Scholar ADE is a phenomenon whereby antibodies bind to the targeted virus and then the resulting antibody/virus complex enhances uptake of the virus by host macrophages and other immune cells. ADE was originally observed with Dengue virus infection and also in the coronavirus feline infectious peritonitis virus (FIPV).2Pedersen N.C. An update on feline infectious peritonitis: virology and immunopathogenesis.Vet. J. 2014; 201: 123-132Crossref PubMed Scopus (150) Google Scholar A relatively overlooked body of ∼40 years of research exists with cats and coronaviruses. Cats infected with FIPV experience dry and wet forms of disease that ultimately result in serious pathologies, including respiratory and neurological issues that are usually fatal.2Pedersen N.C. An update on feline infectious peritonitis: virology and immunopathogenesis.Vet. J. 2014; 201: 123-132Crossref PubMed Scopus (150) Google Scholar Moreover, in cats, it is well known that immunization with feline coronavirus spike protein leads to ADE and, in general, the worsening of infection upon exposure to infectious virus.3Corapi W.V. Olsen C.W. Scott F.W. Monoclonal antibody analysis of neutralization and antibody-dependent enhancement of feline infectious peritonitis virus.J. Virol. 1992; 66: 6695-6705Crossref PubMed Google Scholar, 4Hohdatsu T. Yamada M. Tominaga R. Makino K. Kida K. Koyama H. Antibody-dependent enhancement of feline infectious peritonitis virus infection in feline alveolar macrophages and human monocyte cell line U937 by serum of cats experimentally or naturally infected with feline coronavirus.J. Vet. Med. Sci. 1998; 60: 49-55Crossref PubMed Scopus (68) Google Scholar, 5Vennema H. de Groot R.J. Harbour D.A. Dalderup M. Gruffydd-Jones T. Horzinek M.C. Spaan W.J. Early death after feline infectious peritonitis virus challenge due to recombinant vaccinia virus immunization.J. Virol. 1990; 64: 1407-1409Crossref PubMed Google Scholar Interestingly, in cats infected with FIPV, the expression of ORF7 has been found to be required for macrophage infectivity and ADE, suggesting that coronaviruses have evolved molecular mechanisms to modulate macrophages.6Dedeurwaerder A. Desmarets L.M. Olyslaegers D.A.J. Vermeulen B.L. Dewerchin H.L. Nauwynck H.J. The role of accessory proteins in the replication of feline infectious peritonitis virus in peripheral blood monocytes.Vet. Microbiol. 2013; 162: 447-455Crossref PubMed Scopus (25) Google Scholar Indeed, ADE has been observed to date in several coronaviruses, including CoV-17Wang S.F. Tseng S.P. Yen C.H. Yang J.Y. Tsao C.H. Shen C.W. 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