Working Paper Article Version 1 This version is not peer-reviewed

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

Version 1 : Received: 15 July 2020 / Approved: 16 July 2020 / Online: 16 July 2020 (13:02:40 CEST)

How to cite: Perets, H.; Perets, R. A Preceding Low-virulence Strain Pandemic Inducing Immunity Against COVID-19. Preprints 2020, 2020070352 Perets, H.; Perets, R. A Preceding Low-virulence Strain Pandemic Inducing Immunity Against COVID-19. Preprints 2020, 2020070352

## Abstract

Abstract The COVID-19 pandemic is thought to began in Wuhan, China in December 2019. Mobility analysis identified East-Asia and Oceania countries to be highly-exposed to COVID-19 spread, consistent with the earliest spread occurring in these regions. However, here we show that while a strong positive correlation between case-numbers and exposure level could be seen early-on as expected, at later times the infection-level is found to be negatively correlated with exposure-level. Moreover, the infection level is positively correlated with the population size, which is puzzling since it has not reached the level necessary for population-size to affect infection-level through herd immunity. These issues are resolved if a low-virulence Corona-strain (LVS) began spreading earlier in China outside of Wuhan, and later globally, providing immunity from the later appearing high-virulence strain (HVS). Following its spread into Wuhan, cumulative mutations gave rise to the emergence of an HVS, known as SARS-CoV-2, starting the COVID-19 pandemic. We model the co-infection by an LVS and an HVS, and show that it can explain the evolution of the COVID-19 pandemic and the non-trivial dependence on the exposure level to China and the population-size in each country. We find that the LVS began its spread a few months before the onset of the HVS, and that its spread doubling-time is $\sim 1.59±0.17$ times slower than the HVS. Although more slowly spreading, its earlier onset allowed the LVS to spread globally before the emergence of the HVS. In particular, in countries exposed earlier to the LVS and/or having smaller population-size, the LVS could achieve herd-immunity earlier, and quench the later-spread HVS at earlier stages. We find our two-parameter (the spread-rate and the initial onset time of the LVS) can accurately explain the current infection levels (R^2$\mathrm{=0.74}$; correlation p-value (p) of 5x10^-13). Furthermore, countries exposed early should have already achieved herd-immunity. We predict that in those countries cumulative infection levels could rise by no more than 2-3 times the current level through local-outbreaks, even in the absence of any containment measures. We suggest several tests and predictions to further verify the double-strain co-infection model and discuss the implications of identifying the LVS.

## Subject Areas

COVID-19; low-virulence; high-virulence; pandemic; T-cell; immunity; virus; SARS-CoV-2

Comment 1
Commenter: Zach Matthews
The commenter has declared there is no conflict of interests.
Comment: If a low-virulence strain of the instant coronavirus had spread widely, prior to a mutation into the high-virulence SARS-CoV-2 strain now dominating the global pandemic, would we not see antibody testing results reflecting a far greater proportion of the population having had prior infections than we presently do?
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Response 1 to Comment 1
Commenter: Hagai Perets
The commenter has declared there is no conflict of interests.
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."

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