The United States and many other countries around the world are still debating the rollout of an additional dose, or "booster" shot, of the Covid-19 vaccine. On Friday the US Food and Drug Administration's Vaccines and Related Biological Products Advisory Committee will meet to discuss Pfizer's application to administer a third dose of its Covid-19 vaccine to people ages 16 and older. Though a recent Lancet article advises caution in administering boosters before we have the evidence to fully support that the immunological benefits outweigh any risks, to me, the science seems clear: for those in the US who received mRNA vaccines, a third dose is the minimum we should pursue for Covid-19 protection, and people should prepare themselves for the possibility that they will need additional doses or annual shots in the months and years to come. For those who received the Johnson & Johnson vaccine, there is not enough data so far to say with certainty whether a booster is advisable.
First, let's lay the groundwork for the concept of a three-dose Covid-19 vaccine. Many of the vaccines that are part of our routine immunization schedule in the US are three-dose regimens, or more. Hepatitis B, rotavirus and HPV vaccines are all delivered in three doses, generally with the first two doses closer together and the third one delivered a few months on.
Other vaccines, like ones for diphtheria, tetanus, and polio are four doses or more. Despite the novel delivery system of the mRNA Covid vaccines, it is now clear that their potency wanes over time, as it does for more conventional vaccines. So the fact that our understanding of vaccine-induced Covid immunity has led me to the conclusion that we need a third dose, should come as no surprise.
What is yet to be understood fully, is whether three doses alone will be enough. Science is not static, and our determination of what is needed to protect us against SARS-CoV-2 will change as our understanding of the virus evolves. But if you look at what we know today about the virus and our vaccine-induced and natural immunity, the likelihood is that we will need additional shots.
I wouldn't be surprised to see annual or semiannual shots for Covid-19, at least over the course of the coming few years. The reason for this is not because of the failure of the vaccines but because of the nature of the virus.
Coronaviruses, like influenza viruses, are masters at evading the immune system. Their ecological niche is in long-lived animals with competent immune systems. These animals typically have been infected many times over by the virus' own predecessors. Think of the annual waves of influenza infections and you will have a pretty clear picture of what could potentially lie in store for us with SARS-CoV-2.
Contrary to what many may believe, vaccines do not form an impenetrable shield. Rather, vaccines trigger memory that allows the immune system to mount a rapid response and nip infections in the bud before the virus has a chance to spread within the body.
What we don't know with exact certainty, but we suspect, is that you need a certain level of neutralizing antibodies to stop replication and that the window of time to stop that replication is likely short. This is based on our understanding of the nature of the virus and immune suppression.
To winnow it down to a quick one-liner: SARS-CoV-2 can turn off our body's ability to mount an innate immune response which means, for protection, vaccine-induced neutralizing antibodies must be significant and powerful.
SARS-CoV-2 acts at multiple levels to counteract innate immunity. As a result, a few hours following infection, the majority of proteins produced by the cell are viral, allowing the circulation of more viral particles among surrounding cells. In addition, SARS-CoV-2 suppresses signals that might activate an immune response. This prevents any alarm bells from sounding inside our bodies, buying the virus more time to replicate to high concentrations.
High levels of anti-SARS-CoV-2 neutralizing antibodies can circumvent these mechanisms of immune suppression by attaching to the virus and preventing it from attaching to other healthy cells. No magic number exists in terms of the levels of neutralizing antibodies required for immune protection. But studies of immunity, both from a prior infection and stimulated by a vaccine, suggest that the more antibodies you have, the better.
If the virus has tools that help it sneakily disarm our immune system, then what better way to quell it than with a crushing tidal wave of antibodies that leaves no room for surprises?
This takes us back to the idea of a booster vaccination. Israel is the case study. It was the first country to vaccinate a majority of its citizens against Covid-19. By the end of March, more than half of the population had received two doses of the highly effective mRNA vaccines. In June, all domestic restrictions were removed, including indoor masking, and by early July things looked like they had finally returned to normal. Then, with the arrival of highly infectious new variants like Delta, the tide turned.
A July 31 study found that protection from Covid had faded in proportion to the length of time since vaccination. According to the authors of the study, "Individuals who were vaccinated in January 2021 had a 2.26-fold increased risk for breakthrough infection compared to individuals who were vaccinated in April 2021." What this study told us was that the levels of vaccine-induced neutralizing antibodies mattered, and when antibodies drop, infections go on the rise.
The flicker of hope was that, despite the increase in infections, the vaccines would still work against the variants to prevent severe disease. That hope dimmed somewhat when the Israeli Ministry of Health found in August that almost 60% of those hospitalized with Covid were vaccinated. Just over 60% of the entire population in Israel are vaccinated today.
It should be noted that it is natural that as a nation's vaccination level increases, a higher percentage of its Covid-19 infections will be in vaccinated individuals. What is still unknown are factors such as the severity of those breakthrough infections and the overall health of those who were infected.
Being vaccinated was still better than not being vaccinated when it came to the likelihood of severe disease and death, but it wasn't wholly sufficient to prevent hospitalizations. Israel has already started rolling out a third dose of Covid-19 vaccine. The early data shows a dramatic improvement in defense: after 14 to 20 days, there was a 70-84% reduction in the risk of infection. What that follow-up study from Israel tells us, when combined with the first, is that boosters aren't just an option. They should be considered a necessary third dose of the Covid-19 vaccine.
The need for three doses is increasingly clear. New data released by Moderna shows that a third dose of its vaccine significantly improves antibody levels for all variants, including Beta by 32-fold, Gamma by 43.6-fold and Delta by 42.3-fold.
What's not as clear is where SARS-CoV-2 will lead us from here. We know the virus will change and that new variants will inevitably emerge with regularity, and perhaps be more infectious than the ones that have already taken root.
In addition to the three doses of the current vaccines, we may need to prepare ourselves for the possibility of annual or semi-annual Covid vaccines in the years to come, and the possibility that other means of protection -- mask-wearing, testing and quarantine, and the development of prophylactic treatments and drugs -- might need to be used for many, many months to come. In the end, the major determinant of our ability to control Covid-19 is human behavior, not the behavior of the virus itself.
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