A Preceding Low-virulence Strain Pandemic Inducing Immunity Against COVID-19

Comment: This is an important question that we discuss in the paper, in particular, the issue of serologic testing and the issues of humoral and cellular immunity. In brief, as discussed in the paper, we should have expected the majority of people to show antibodies to the LVS. Current serologic tests typically show up to a few percent of the population to have SARS-CoV-2 antibodies. This suggests that current tests do not identify antibodies for the LVS. However, current serologic tests are optimized for the known SARS-CoV-2 and might indeed not necessarily be expected to identify the LVS. Moreover, antibodies levels might be depleted on short timescales of a few months, and given the earlier onset of the LVS, they might not be identified. Even more likely, however, is that the main immunity is cellular rather than humoral, as we suggest in the paper. In fact, recent findings show T-cell response in people with negative serologic tests (e.g. the recent Sekine et al. 2020).

Below is the relevant extract from the paper (pages 6-7), discussing these issues in more depth.
"Cross antigenicity between the LVS and COVID-19 is an essential part of our model and can be either humoral or cellular. If cross antigenicity relies on cross-reactive antibodies, it is possible that antibodies to LVS will be detected by serological testing for SARS-CoV-2, already employed to some extent in several countries[#Ioa+20]. In particular, countries which appear to have achieved LVS herd-immunity should have shown a large fraction of the population to be seropositive, in contrast with the currently directly measured lower per-population HVS infection-levels[#Ioa+20, #Hav+20]. However, current serologic testing is optimized for HVS and might be less efficient for the detection of the LVS. Recent findings at the levels of a few percents up to 30 percent seropositive, i.e. tens to hundred times larger than the infection rates inferred from the confirmed cases, but still considerably lower than required for herd-immunity. These likely reflect low-testing levels in most countries, suggesting that actual HVS-infection levels are typically much higher than inferred from the reported cases, consistent with our use of testing-normalization in our analysis (see Methods). It also suggests that none of the currently identified genetic groups of SARS-CoV-2 could be the LVS proposed here. Moreover, it is important to note, that it is currently unclear whether the antibodies detected in the currently available serologic tests are indeed protective antibodies, and therefore even in the cases of humoral cross antigenicity, LVS strains might not be detected at all by SARS-CoV-2 serologic tests. We, therefore, suggest making use of a more direct and accurate method to test the existence of LVS antibodies, by employing a viral micro-neutralization testing of the HVS on serum from a sample of people (preferably from highly exposed countries, for which the majority of the population should already have been infected by the LVS) who are found to be negative for the SARS-CoV-2 HVS in serologic tests. These should be able to identify antibodies reaction to the HVS otherwise undetected by currently employed serologic test, in a similar manner as used to test acquired immunity to a high pathogenic flu virus following vaccination for a less pathogenic flu virus[#Ste+05]. To the best of our knowledge, only one micro-neutralization study (with limited statistics) has been done on SARS-CoV-2 to date[#Man+20], not identifying antibodies in the serum of people who were found to be negative for the SARS-CoV-2 HVS in serologic tests."