Abstract
It has now been 1 year since I took over as editor in chief of Viral Immunology, so it is quite fitting that we now present our second special issue on coronaviruses as I celebrate that 1 year anniversary. This issue is focused on therapeutics and pathogenesis, and it is astounding to consider how much more we know about this virus and its disease than we did 1 year ago. As data emerge on real-world vaccine effectiveness and its potential impact on virus transmission, we can begin to answer questions we have been pondering since the beginning of the pandemic. Unfortunately, the answers are not always simple, and we too often find ourselves responding with qualifying percentages rather than a hard yes or a no.
The title of this editorial is clearly a double entendre, because from the beginning of the pandemic, before it was even called a pandemic, there was a spectrum of response even to the emergence of the virus itself. Upon hearing about the introduction of this virus into the human population, individuals responded differently, with responses ranging from fear, and even paranoia, to absolute indifference. Unfortunately, this spectrum of response went all the way up to governments and countries, which ultimately contributed to a very broad spectrum of public health threat and urgency in different places around the world. For example, as I write this piece, all eyes are on the unexpected and unfortunate situation in India. However, the spectrum I am referring to here is the spectrum of the immune response against the virus and the vaccines we are now using to fight it.
Herd immunity itself, although perceived by some as a state that can potentially be reached by a defined percentage of vaccination of the public, is really a spectrum. It is somewhere along that spectrum that herd immunity is established and becomes effective, but we do not yet know where that point is for this pandemic, and within that spectrum there can exist different putative or desired end points. Do we want enough herd immunity to remove the necessity for lockdowns and restrictions on social gatherings? Or are we aiming for a level of herd immunity that will effectively eliminate the virus from our communities? These are very different goals.
If we consider the human immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, there is an obvious spectrum of response to the virus. Some infected individuals experience an asymptomatic infection, others mild symptoms, whereas some get severely ill and even succumb to coronavirus disease 2019 (COVID-19). There also appears to be a range of transmission potential based on the age of the infected individual. If it proves true that most children <10 years of age really do not get very sick from SARS-CoV-2 infection, then why is that? Might it be because they do not mount a strong immune response, meaning they do not experience massive lung inflammation or a cytokine storm? In contrast, teenagers and young adults typically experience mild symptoms, but seem to be efficient spreaders.
The only obvious binary aspect of SARS-CoV-2 infection is the infection itself. Once exposed, we are either infected or not, and it would be great if the vaccines we have available actually prevented the virus from infecting anyone who receives a vaccine, but they do not, at least not for everyone. At this point we do not have sufficient data to know what percentage of vaccinated individuals are truly immune to actual infection, and perhaps one vaccine is better in this regard than others might be, but it will be some time yet before we know how well any of the vaccines establish proper sterilizing immunity.
There also exists a spectrum of potential desired effects of mass vaccination. Since the currently available vaccines do not confer 100% neutralizing ability, the question is what should we be hoping to achieve? Virologists and immunologists will always want, and strive to create, the perfect infallible vaccine, but governments and public health agencies are likely satisfied with a vaccine that keeps infected individuals alive and out of hospitals. This means there is breadth in what different stakeholders might want from an immunization program, ranging from complete elimination of the virus, to a situation in which immunized individuals have a head start in the race against the virus.
Since we first began to analyze antibody levels and study their potential decline postinfection, and now the levels of antibodies resulting from vaccination, it has been clear that there are varying levels of antibodies in the blood of infected or vaccinated individuals. Is there an antibody level, or perhaps a certain type of antibody, which will correlate with protection from infection or even from developing severe disease? Are antibodies even the key determinant? Perhaps the T cells are the key, and extensive study of T cell function will reveal the true correlate of protection, or is immune protection a multifactorial spectrum involving antibodies and T cells in combination? There are fascinating questions remaining to be answered, and never before have so many people in the world been so keenly interested in basic virological and immunological questions.
Currently, with many countries coming close to what they have set as a goal for herd immunity based loosely on percentage population vaccinated, whether or not vaccination will prevent transmission is the major question. Emerging evidence suggests that vaccination can reduce transmission by ∼50%, which presents another spectrum. What determines whether or not an infected vaccinated person can transmit the virus to another person? Presumably, the viral load in the infected individual will be a factor, but we also know that can vary.
Finally, we cannot, and must not, forget the virus itself and its extremely dynamic capability to adapt and change. This virus is still figuring out its new host, and at this point, it is impossible to predict how it will continue to do so. The variants themselves represent another relevant and important spectral consideration. By now, the virus is evolving so extensively that we already categorize variants based on our level of concern, that is, variants under monitoring, variants of interest, and variants of concern (VOC). The mutations associated with VOC are responsible for a range of ability to spread, as well as a variable impact on vaccine effectiveness. The phenotyping of these variants and the mechanisms associated with the different mutations will give us an idea as to how these mutations afford the numerous variants their superpowers. We already know that some key mutations enhance the binding of spike to ACE2, whereas others reduce antibody binding to spike, but so far we have focused on mutations in spike in part because this is the target of all the vaccines. We are already seeing emergence of mutations outside of spike that could potentially enhance viral fitness. We know there are antibody and T cell epitopes in many other SARS-CoV-2 proteins, so might we see immune escape variants in other proteins, such as nucleocapsid, for example?
In closing, the answers are coming as fast as the questions arise. The pandemic seems to be subsiding, at least in some parts of the world, and now that we have multiple vaccines being dispensed in large scale, it is time to look ahead to figure out what the coming years will look like. The currently available batch of vaccines seems to be getting us out of the pandemic, but no one can really be sure what next year will look like. The only thing we can be certain of is that science will keep fighting this virus, and science will win in the end. We just do not know yet when that end will come.