The uncertainties underlying herd immunity against COVID-19

Herd immunity happens when a relatively large proportion of a population becomes infected by an agent, subsequently recovers, and attains immunity against the same agent. That proportion thus indirectly protects the naïve population by preventing the spread of the infection. Herd immunity has been suggested to interrupt and control the COVID-19 pandemic. However, relying on establishing herd immunity can be catastrophic considering the virulence and lethality of SARS-CoV-2. Meanwhile our understanding of the pathogenesis, case-fatality rate, transmission routes, and antiviral therapy for COVID-19 remains limited now. Interrupting or slowing the COVID-19 transmission seems more opportune than vaccination, antiviral therapy, or herd immunity, all of which will take some time to yield. Thus, social distancing, face-masking, and hygiene are the most appropriate immediate countermeasures. Because the social fabrics, economic implications, and local demands of various nations are unique, early relaxation of restrictions may seem hasty particularly when fatality rates are high, or when the healthcare systems could be inadequate or become inundated. Conclusively, avoiding any overwhelmingly risky approach in fighting the pandemic is prudent.

Some epidemiological features of the virus, such as its global spread and infectivity-also likely by the unpredictable asymptomatic carriers [39] and subjects with milder respiratory symptoms or with subclinical manifestations [39]-could have been boosted by the stability and persistence of the virus in the environment [14]. Forty percent of the cases may have been due to transmission by the asymptomatic carriers [40]. The COVID-19 experiences of Italy and South Korea support the unpredictable nature of the pandemic [14, 41,42]. While the entire uninfected population in the five continents are likely immune-naïve and susceptible to the virus, continuous caution and preparation are needed for controlling subsequent incidence peaks of the infection because not all regions have been restricted, and when easing of restrictions and reopening of economies will inevitably ensue. Both aggressive and widespread contact-tracing for early detection of the cases should continue to reduce the disease burden nationally and internationally [8]. Thus far, the countermeasures implemented to deal with the COVID-19 outbreak have included in-house self-isolation, barring mass-gatherings, working from home, remote or online teaching/learning, development of potential vaccines or antiviral agents, and reliance on the emergence of herd immunity [43,44]. All these approaches have their limitations and strengthens. In this Communication, we summarize the uncertainties shrouding the herd-immunity concept in tackling the COVID-19 pandemic. Encouraging or discouraging herd immunity is a pivotal public-health debate in the fight against SARS-CoV-2.

Herd immunity against COVID-19
When a large fraction of a population is infected by a certain microorganism-naturally or by vaccination-and recovers afterwards, the individuals' immune systems are expected, collectively, to thwart subsequent exposures; this phenomenon is called herd immunity [45,46]. During the COVID-19 pandemic, the British government was the first to refer to this strategy, but later withdrew their proposal following the strong criticism by the scientific and medical communities and social media [47,48]. A slightly similar approach was adopted by the Dutch and Swedish governments. This concept is now challenging the public-health decision-makers in several other countries. Intervening by herd immunity implies that some people may have to host the virus potentially for months while no vaccine or efficient antiviral drug is available. This consideration seems risky despite some researchers' showing that an immune response could be induced against SARS-CoV-2 infection in the experimental ferrets, rhesus macaques, and in the COVID-19 patients [49][50][51]. Therefore, letting herd immunity take control is a well-grounded postulate.
The course of the pandemic in Iran, which was one of the first countries that was hit hard by the first peak of this outbreak, is potentially a good example. Figure 1 shows two incidence peaks of the epidemic in Iran. These are unfortunately mirrored by a similar trend in the fatalities, suggesting that a proportion of the 80 million Iranian residents may have attained herd immunity gradually; otherwise, hundreds of thousands more people would have succumbed to the rapid viral spread by initially reported case-fatality rates (CFRs). However, extensive serological testing of the population is necessary to confirm this postulate.
Meanwhile, the present general evidence on production of antibodies in symptomatic or asymptomatic subjects and the longevity of such antibodies against SARS-CoV-2 has been debated [52,53]. Also, some relevant aspects of the pathobiology of the virus are still unknown. For example, the definite mortality rate due to COVID-19 will take time to be determined. Estimates suggest this to be around 8% in some populations [54]. However, considerable differences in the CFR have been recorded in different regions because of the variations and inconsistencies in the level of the public-health measures or healthcare. High fatality rates could also reflect comorbidities [55] that complicate patients' vulnerability and prognoses. Information on the CFR is crucial for determining the effectiveness of herd immunity in the fight against the pandemic. For herd immunity to succeed, 60-70% [56] or 80% of a regional population should ideally be infected and subsequently survive the disease. Providing effective and long-lasting antibodies and immune memory are produced and maintained, one can only hope to reach a certain number of immune people in the face of the fatalities. However, this will take a relatively long time with potentially many lives lost along the way. Letting the virus loose to cause loss of lives is grossly unethical. Immunologically, SARS-CoV-2 is new to humans; thus, grave outcomes are expected as have been documented throughout the world so far. As of 30 June 2020, 10,278,458 positively confirmed cases with almost 480,000 death toll proves the widespread and successful dissemination of the virus. The cumulative knowledge about COVID-19 suggests that its pathogenesis and virulence differ from other viral or bacterial infections so that it may not be controlled by herd immunity. The present lack of knowledge on the pathogenesis, CFR, transmission routes, and lack of antiviral therapies, or lack of vaccination [8] reduces the potential of herd immunity to succeed, at least during the present pandemic. Accordingly, the British Society for Immunology has called for caution [58].
Moreover, the asymptomatic COVID-19 carriers may unintentionally and unknowingly transfer the virus to vulnerable subjects who may eventually suffer severe prognoses [39]. Recent clinical findings suggest that patients with comorbid hypertension, diabetes, cardiovascular diseases, chronic respiratory diseases, and cancer suffer high CFRs [8]. However, data on the viral distribution and antibody production among the potential high-risk or low-risk hosts are lacking. Understanding Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 8 July 2020 doi:10.20944/preprints202007.0159.v1 the virulence of the virus is also challenging. Will the virus become more virulent upon evolving with potential mutations while transmitting within a population? The high possibility of seasonal recurrence of COVID-19 should be considered together with the potentially unstable genetic/genomic characteristics of SARS-CoV-2; similarly to influenza virus, SARS-CoV-2 may evolve by mutations as it may re-emerge seasonally or regionally [59,60]. Future epidemiological and genetic/genomic studies of the virus may decipher the viral mutation rates and will potentially direct the design and testing of a vaccine against COVID-19.
With the above caveats, reliance on herd immunity now will likely cause a major public-health catastrophe. Many countries will need many hospitals and intensive-care resources to successfully manage the surging numbers of the succumbing COVID-19 patients [61,62].

Conclusions
Maintaining the balance between the economic repercussions of the restrictions and saving the human lives and livelihoods is a social, ethical, and political debate during the present pandemic. Subsequent to the disagreements and deep concerns raised by the Olympians and their governments, the International Olympic Committee finally announced to postpone the 2020 Tokyo Olympic Games to 2021 [63]. This announcement agrees with the presently recommended physical-distancing and hygiene countermeasures, and active contact-tracing, which are important particularly when the exact CFR is yet unknown. Early easing of the restrictions and reopening of the economies in some of the countries like Iran may lead to a second incidence surge of the pandemic. Reconsidering and revising the public-health policies for managing the COVID-19 pandemic is mandatory. According to one of the latest WHO COVID-19 Situation Reports, almost all of the countries are now invaded by SARS-CoV-2 [6]. Thus, aggressive contact-tracing and shutting down social venues and gatherings will likely prevent the viral spread, though a fraction of the population may expectedly be exposed to SARS-CoV-2 as economies gradually reopen. Interruption of the transmission chain now is arguably easier, timelier, and more practicable than pursuit of herd immunity or development of antiviral or prophylactic therapies-which take longer to yield. Thus, the fight against this pandemic requires pragmatic measures instead of miscalculated, idealistic decisions.