During the past two decades there have been three major coronavirus spillovers. The severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) pandemic from 2002 to 2004 and repeated Middle East respiratory syndrome coronavirus (MERS-CoV) outbreaks since 2012 were brought under control by mitigation measures. A large number of SARS-related coronaviruses have been discovered in bats, their natural reservoir host, and SARS-CoV-2 emerged on December 31, 2019 [1] resulting in over 770 million cases and nearly 7 million deaths globally [2]. Lockdowns and other measures were implemented in the spring of 2020 and highly effective vaccines were rapidly developed and deployed starting in late 2020. Despite these efforts, SARS-CoV-2 will likely continue to circulate endemically in human populations, undergoing antigenic evolution in different regions with variants emerging under immune selective pressure [3].
Long before the emergence of SARS-CoV-1 and − 2 and MERS-CoV, four human coronaviruses (hCoVs) have circulated endemically. These include two betacoronaviruses, OC43 and HKU1, which are of the same genus as SARS-CoV-1, -2, and MERS-CoV, and two alphacoronaviruses, 229E and NL63. The average age of first infection with OC43, HKU1, 229E, and NL63 is 5 years [4], and individuals are frequently reinfected with the same virus over the course of their lives [5–7]. HCoV infection usually results in the common cold, characterized by coryza, sore throat, headache, fever, and cough [8]. The four hCoVs are estimated to have emerged between 50 and 700 years ago [9, 10]. Like SARS-CoV-1 [11] and SARS-CoV-2 [12], hCoVs such as 229E evolve antigenically, escaping immunity induced against earlier circulating strains [13]. Multiple distinct lineages circulate, with two known lineages each of HKU1 and OC43. HCoVs OC43, HKU1, 229E, and NL63 are thought to be endemic globally, although variation has been described in seroprevalence between the Americas, Africa, and Europe [14, 15].
Given the recent SARS-CoV-1 and − 2 and MERS-CoV spillovers, why are there not more circulating endemic hCoVs? It has been suggested that existing population immunity could restrict entrance of novel coronaviruses [10]. Numerous early studies during the COVID-19 pandemic explored whether hCoVs modulate SARS-CoV-2 infection and disease risk and explain reduced severity of COVID-19 in children compared to adults [16]. There are cross-reactive epitopes between the hCoVs and SARS-CoV-2 spike, especially in the S2 segment [16, 17]. Studies in adults and mice showed minimal effect of prior hCoV infection on SARS-CoV-2 infection risk [18, 19], although recent infection may protect against a COVID-19 case [20, 21]. However, pre-pandemic samples from children and adolescents were found to have higher levels of cross-neutralizing SARS-CoV-2 antibodies than older individuals [22, 23], although not in all studies [24]. Children also have higher pre-pandemic IgM responses to SARS-CoV-2 and other hCoVs, whereas antibodies to these antigens in the elderly were predominantly IgA or IgG [18, 25]. Additionally, young adults have been observed to have OC43- or NL63-induced IFN-gamma secreting T cells that cross-react with SARS-CoV-2, while older adults do not [26]. This pattern has not been observed for influenza or RSV, suggesting the effect may be coronavirus specific [26]. Together, these data suggest that adolescents compared with other age groups may be more likely to have levels of endemic hCoV immunity that could restrict SARS-CoV-2 infection, if such protection exists.
As COVID-19 transitions to an endemic disease [27], a second question is whether SARS-CoV-2 might drive other hCoVs to extinction. Each new emerging SARS-CoV-2 variant is more transmissible [28, 29], making it plausible that SARS-CoV-2 may outcompete existing hCoVs. The control restrictions put in place during the COVID-19 pandemic resulted in the lowest reported incidence of common respiratory illnesses, such as influenza A and B viruses as well as RSV disease [30]. While most of these viruses rebounded once restrictions were lifted, some lineages may have gone extinct while restrictions were in place. For instance, it has been proposed that the pandemic dramatically reduced circulation of the Influenza B/Yamagata lineage, one of the two major influenza B lineages to circulate globally prior to the pandemic [31, 32], because it had a lower basic reproduction number. Whether such competition exists between SARS-CoV-2 and the hCoVs remains to be fully elucidated. A modeling study explored different scenarios of cross-protection between SARS-CoV-2 and endemic coronaviruses and found that intermediate cross-protection between viruses would lead to less frequent but larger hCoV epidemics while high cross-protection might eliminate hCoV transmission, with SARS-CoV-2 outcompeting the hCoVs [7].
Since 2017, we have followed a cohort of adolescents in the Cebu province of the Philippines. The first confirmed COVID-19 case in the Philippines was reported on January 30, 2020 and the government implemented a pandemic mitigation strategy consisting of lockdowns, quarantine, COVID-19 testing, hospital control, and economic relief starting in March 2020. Over 4 million cases and 66,000 deaths have been documented nationwide in outbreaks occurring in several waves [33]. Epidemics in Cebu Province mirrored those seen nationwide. Mass COVID-19 vaccination was started in adults in March 2021 and adolescents in November 2021. The objectives of this study were to: (1) assess the seroprevalence and level of immunity to the four hCoVs in Cebu, Philippines before and during the COVID-19 pandemic but prior to vaccination, (2) test if differences in immunity to the hCoVs were associated with the odds of infection with SARS-CoV-2, and (3) evaluate the level of boosting to hCoVs after infection with SARS-CoV-2.