key: cord-0843038-wx1m00f5 authors: Yewdell, Jonathan W. title: Individuals cannot rely on COVID-19 herd immunity: Durable immunity to viral disease is limited to viruses with obligate viremic spread date: 2021-04-26 journal: PLoS Pathog DOI: 10.1371/journal.ppat.1009509 sha: 0e35ec3003358e7475012303a99617e5d7f89815 doc_id: 843038 cord_uid: wx1m00f5 nan natural respiratory infections with measles or variola (smallpox) viruses, famous for inducing life-long immunity to disease, do not prevent respiratory reinfection, which though asymptomatic and nontransmissible, can be detected by increased antiviral antibody titers [7, 8] . What polio-, variola, and measles virus share is dissemination from the initial infection site via lymph and (secondarily) blood as an obligate step in pathogenesis or transmission. Virusprogrammed interorgan dissemination occurs in stages over days, as the virus productively infects one organ and proceeds to the next via lymph and blood [9] . Table 1 [10] summarizes the protection conferred by natural infection/vaccination for 20 common human viral pathogens. Blood/lymph-based dissemination or tropism is clearly implicated as the critical vulnerability of viruses to infection/vaccination-induced immunity. By contrast, immune memory routinely fails to control viral reinfections on mucosae. At first glance, this might be surprising, as 90% of synthesized antibodies (the vast majority being immunoglobulin A (IgA)) are delivered to mucosae. Yet selective IgA deficiency, the most common inherited immune deficiency in Caucasians, has modest effects on susceptibility to mucosal viruses [11] . This suggests that evolution may have focused antiviral immunity on preventing virus dissemination via body fluids rather than blocking mucosal infection. Antiviral antibodies are present at relatively high concentrations in blood and lymph, where they can function directly by neutralizing viral infectivity and indirectly via Fc-mediated viral clearance by phagocytic cells and natural killer (NK) cell killing. Phagocytic clearance is particularly effective in the lymph nodes, which evolved in part to eradicate particulate pathogens. Critically, limiting virus dissemination in body fluids blocks virus pathogenicity in endorgans and prevents end-organ participation in viral transmission. While vaccines are unlikely to provide long-lasting sterilizing immunity to CoV-2, they should durably reduce viral replication in the upper airway and prevent, or at least attenuate, Although the degree to which the Moderna and BioNTech mRNA vaccines owe their remarkable protectiveness is due to humoral versus cellular immunity remains to be determined, the extremely robust antibody response they elicit is consistent with a major role for neutralizing antibodies in disease protection [12, 13] . Why does the immune system have difficulty controlling mucosal viral infections? In part, this may be due to the wiliness of viruses, whose survival requires staying one step ahead of host immunity. As the skin provides an extremely effective physical barrier to viruses, typically only breached by insect bites, mucosae are the primary site of viral transmission. Mucosae are replete with immune tissues that possess the bulk of antibody-secreting B cells. Most mucosal antibodies function to control the commensal cellular microbiome, which requires constant shepherding lest it overwhelm the host. Enteric viruses can bind to bacteria to enhance attachment and infection of epithelial cells [14, 15] . Could this also shield them from antibodies? Several other possible factors contribute to the limited human mucosal immunity to virus reinfection. First, until approximately 10,000 years ago, humans evolved in isolated small populations, and viral infections were likely mostly limited to viruses capable of vertical transmission (herpesviruses, papillomaviruses) and arboviruses (i.e., transmitted to the blood by insects). Under these conditions, there may have been little selection pressure to deal with horizontally transmitted viruses that infect mucosae. Comparing mucosal immunity between vertebrates that evolved in small versus large population clusters may reveal immune mechanisms that more effectively control mucosal infections, leading to insights for improved vaccination and treatment. Second, the immune system may have evolved to permit viral mucosal infections. If mucosal infection was a significant threat to host reproduction, wouldn't innate antiviral mechanisms (e.g., type I interferon (IFN)-stimulated genes) be employed constitutively in mucosae rather than conditionally? Although antiviral cytokines exert potent effects on the nervous system that would impact evolutionary fitness if present chronically (fever, malaise, etc.), it seems likely that evolution could have crafted a solution to localize innate antiviral effects. Could virus-mediated horizontal gene transfer provide sufficient evolutionary advantages to temper antiviral immunity [16] ? Could limited, but repeated, mucosal infections play a role in maintaining basal immunity to more serious pathogens, as described for chronic herpesvirus infections [17] ? With better understanding of immunity, it may be possible to develop vaccines that provide far more robust immunity than natural infections and overcome mucosal immunity's limitations. An example is the effectiveness of the Salmonella typhi Vi capsular polysaccharide vaccine, which targets a bacterial component nonimmunogenic in natural infections. Indeed, it is possible that mRNA immunization provides more durable protection than SARS-CoV-2 infection, given that vaccination induces higher antibody titers than infection [18] . The cost of developing effective vaccines to the many present (and future) mucosal viruses that plague humanity is a pittance relative to the havoc caused by our ignorance. COVID 19, as terrible as it has been, should be a wake-up call: Far more dangerous viruses lurk in nature. Evidence for adaptive evolution in the receptor-binding domain of seasonal coronaviruses OC43 and 229E Prospective mapping of viral mutations that escape antibodies used to treat COVID-19 Occurrence and frequency of coronavirus infections in humans as determined by enzyme-linked immunosorbent assay The time course of the immune response to experimental coronavirus infection of man Rapid Decay of Anti-SARS-CoV-2 Antibodies in Persons with Mild Covid-19 Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies Observations made during the epidemic of measles on the Faroe Islands in the year 1846 Smallpox and Its Eradicaiton. World Health Organization Mims' pathogenesis of infectious disease Vaccination against the major infectious diseases. C R Acad Sci III Selective IgA Deficiency: Epidemiology, Pathogenesis, Clinical Phenotype, Diagnosis, Prognosis and Management Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine Bacteria facilitate enteric virus co-infection of mammalian cells and promote genetic recombination Virus interactions with bacteria: Partners in the infectious dance The good viruses: viral mutualistic symbioses Herpesvirus latency confers symbiotic protection from bacterial infection COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses Brian Kelsall (NIAID) generously provided insightful suggestions on mucosal immunity.