Abstract
With the advent of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), vaccine development was initiated with a lofty goal to prevent morbidity and mortality from infection. Results soon put into perspective the challenges associated with defining whether a COVID-19–directed vaccine works. 1 Vaccine results were presented in terms of four main topic areas: effectiveness of preventing infection, illness (death), hospitalizations, and preventing onward transmission of the virus.2–5 These topic areas soon found their way into health policy and social media discussions.
It is perhaps the latter topic area that perplexes policy makers the most since guidelines for quarantining and mask requirements reflect a perceived “transmissible viral load.” If one tests positive for COVID-19, how many days of self-isolation are required to prevent exposing others? 6 Does wearing masks prevent being infected or prevent the spread of the virus? 7
So, what was the intent of the first featured COVID-19 targeting vaccines that came under emergency use authorization and subsequent approval by the U.S. Food and Drug Administration (FDA)? One can argue that antibody targeting the SPIKE protein was a means to block the interaction with the angiotensin-converting enzyme 2 (ACE2) receptor of the host with the hope of preventing virus transmission. Although the SARS-CoV-2 requires ACE2 to infect cells, the precise relationship between individual(s) ACE2 levels, ACE2 polymorphisms, viral infectivity, and severity of infection is still not well understood.
Targeting this interaction falls under the premise associated with mechanisms of antiviral drugs. This includes the increase of a cell's resistance to a virus and suppression of virus adsorption on the cell or its diffusion into the cell.8,9 The development of antibody cocktails used therapeutically highlights this point. 10 Therefore, targeting the ACE2 interaction was going to positively impact on illness and presumably death but not prevent virus transmission directly.
Variants are often presented in social media as viral waves, the first two being Alpha and Delta. We are presently in the Omicron wave with some countries reporting that the population of individuals with symptomatic COVID-19 is increasing despite having high vaccination and acquired immunity rates. This alone suggests that despite vaccination and counting those who have experienced acquired immunity through natural infection, the disease will not be irradicated. Although the early waves of Alpha and Delta relied on increased transmission of the virus, the Omicron driver adds to that viral escape.
Early on there was suspicion that viral escape of neutralizing antibodies by SPIKE protein variants was going to be problematic. 11 Just targeting the SPIKE protein and not viral core elements can be a mechanism with the result of a limited immune response. 12 However, antigen sin is also plausible.13–15 Should we then be surprised and disappointed that even after vaccination individuals can be infected by coronavirus variants.
We have learned from innate immunity to viruses that pattern recognition is fundamental for adequate immunity, 16 however, even previously infected individuals are getting symptomatic COVID-19. Being exposed and generating an acquired response to a variant of SARS-CoV-2 is not enough as some individuals are infected multiple times. Although protection against severe disease is evident, especially among those with acquired immunity, how long this protection lasts is an open question.
Perhaps we have entered a time wherein we will learn to coexist with the virus, being satisfied that the merits of vaccination and acquired immunity are to limit severe illness and hospitalization and not prevent virus transmission. Consequently, there is now a longstanding argument for minimizing contact with infected people to help reduce transmission, since the perception is that stopping transmission will make the virus “go away.”
“Going away” is not what is happening. The virus is endemic, just like coronaviruses in general associated with the common cold. The endemic nature of the virus affects both public policy and practical strategies. The endemic nature of the virus might suggest we no longer indiscriminately self-test for COVID-19 to determine whether we have contracted COVID-19. There are statistical guidelines as to when testing should commence using home kits and how long should one quarantine. But what is the goal of self-testing and quarantining if you do not test positive?
From a policy perspective, it is easy to think that transmission would be thwarted when enough symptomatic individuals complied with home confinement at symptom onset. There is some research on the effect of voluntary self-isolation on viral outbreak control in the absence of viral treatment. 17 A conclusion reached is that the effect of voluntary self-isolation decreases substantially with the proportion of asymptomatic infections increasing. 17 It is widely believed that asymptomatic infections are one of the major sources of influenza transmission, which most likely applies to SARS-CoV-2 transmission. A conclusion of such studies is that with a rise in the frequency of asymptomatic infections, the effectiveness of voluntary self-isolation will become very limited, requiring other ideas and strategies to be evaluated to contain onward transmission.
The pandemic is not over as SARS-CoV-2 is not as predictable as we would like and the idea of herd immunity to limit transmission is not prevailing. Consequently, the hunt for pan-coronavirus vaccines, nasal vaccines, and rapid manufacturing technologies for variant specific vaccines will continue. 18 Since vaccinating every 3 months is not feasible, a yearly boost like that for the flu is reasonable. The world has learned to manage and live and with the flu, although ∼12–60 K people die yearly from flu complications. We can learn to live with SARS-CoV-2, but like the flu, for some, there will be a cost.
Our experience in the past 2 years draws attention to the fact that asymptomatic infection, short postvaccinal post-nfection immunity, and the mode of transmission of the SARS-CoV-2 variants preclude successful eradication and the virus that will continue to circulate like the flu virus. This is a justified conclusion, supported with published data and is shaping as the prevailing concept underlying the strategies for managing this infection in the future. Therefore, it is worth putting it on the table for in-depth discussion for the brainstorming the better management of COVID-19.
It would be interesting to have models considering the comparison between the genetic variability of SARS-CoV-2 and the flu virus to predict the coronavirus capacity to continue to present new variants and even new strains at the rate the flu virus does. What would the consequences of a lower variability be? Would the coming variants exhaust their options for escape? In this respect, keeping the intensity of the waves of the pandemic low, especially restricting its access to immunocompromised patients, will greatly reduce the rate of occurrence of new variants. Maybe it is worth discussing once again the necessity of better antivirals for the treatment of COVID-19 (even mild) because this would further decrease the probability of mutation. The models should quantify the probability of this scenario that would diverge from that of the flu in the long run.