Do you really need to be boosted to be protected?

Will we need to get vaccines periodically?

CLINICAL MATTERS

With the seemingly unending emergence of new Covid-19 variants, many people are starting to question whether the pandemic will truly end. Despite an unprecedented vaccination rollout, daily case numbers remain in the thousands and many people are still testing positive for SARS-CoV-2. How many boosters do we really need? Do vaccines still work after three months? Will we need to get vaccinated periodically to continue to keep society open?

There has been so much misinformation on social media and mainstream media that many people are convinced that the only way for them to stay healthy is to keep getting booster shots. This is completely false, and mistakenly equates antibody levels to protection against Covid-19. 

To review, vaccines protect people in three different ways. A vaccine can prevent infection, decrease the risk of severe disease, and prevent transmission. Most people equate vaccine efficacy with the ability to prevent symptomatic infection. This is, however, not the only way vaccines work and this misunderstanding is often exploited by anti-vaxxers who point to breakthrough infections as “proof” that vaccines are useless.

To understand how vaccines against Covid-19 protect us, it is important to look at the different parts of the immune system that are activated by the vaccine. The immune system has many different parts, most of which are interconnected with each other. The two most relevant parts of the immune system that are involved in vaccine protection are the B-cells, which produce antibodies, and the T-cells, which kill viruses in infected cells.

Antibodies against viruses or bacteria are like little guided missiles, which attach to parts of the pathogen. In order to make antibodies that target a microbe, a vaccine contains a piece of the organism that can be recognized by the body as foreign. In the case of mRNA vaccines, the mRNA in the vaccine contains instructions for the body to make a viral protein that the body then makes antibodies against. For SARS-CoV-2, the target for most vaccine-generated antibodies is the spike protein. Since the spike protein is the part of the virus that is used to enter and infect a human cell, an antibody sticking to this spike protein can prevent the virus from infecting the target cell. It “neutralizes” the infectiousness of the virus, hence the term neutralizing antibody. During natural infection or when whole inactivated virus (Sinovac, Sinopharm) is used, the body makes spike protein antibodies along with antibodies against other parts of the virus. These antibodies that target non-spike parts of the virus, however, are not neutralizing. They can still help the body recognize and eliminate the viruses through other means, but they will not prevent infection. 

T-cells, on the other hand, come in a variety of flavors. The most well-known function of T-cells is to kill cells that are already infected by an organism. Since antibodies only work when a pathogen is outside a cell, the T-cells are like the body’s policemen that can find viruses and bacteria already inside cells. When a T-cell, specifically a cytotoxic T-cell, recognizes a virus-infected cell, it destroys the cell and the viruses inside it. While T-cells are also generated in response to spike protein from vaccines, other parts of the virus can generate good T-cell responses. Natural infection and whole inactivated virus vaccines generate not just spike-protein recognizing T-cells, they also generate a wide variety of T-cells that can recognize different parts of the virus. This makes natural infection and whole inactivated virus vaccines more likely to retain activity against new variants. Because T-cells only work against virus-infected cells, they do not prevent infection but instead decrease the risk of severe disease. As a bonus, T-cell responses tend to last a very long time. Much longer than after antibody levels have gone down. This means that protection against severe disease by vaccines is expected to be less vulnerable to new variants. This protection seems to last for at least one year, potentially longer when given one or more booster shots.

To recap, B-cells produce antibodies that can prevent infection but are limited to neutralizing antibodies against the spike protein. These are relatively short-lived and are vulnerable to new variants. T-cells do not prevent infection but are very good at preventing severe disease and death. This protection lasts a long time after being fully vaccinated and receiving at least one booster shot. T-cells are less vulnerable to variants.

Given these circumstances, what is the best way toward endemicity? With the high coverage of vaccination, it is likely that endemicity has already been achieved. Despite the emergence of new variants, our current vaccines continue to protect against severe disease, thanks to our T-cells. We will never be back to the immune-naïve state from two years ago. Even with “waning” antibody levels, a vaccinated person is never back to zero. Looking at deaths among those infected with Covid-19, even non-boosted individuals are much less likely to die compared to unvaccinated persons (Figure 1).

The question then becomes: What is the ideal number of doses and boosters needed to ensure deaths and severe cases stay low? As the graph shows, the incremental benefit of preventing deaths is highest between vaccinated and unvaccinated populations. The differences in mortality rates for no booster, booster, and two boosters aren’t all that far apart, and are likely less significant among the lower risk populations. This is why a second booster using the old vaccine formulations is not yet recommended for the general population, since the added benefit of more boosters is uncertain. In addition, the mismatch of BA.5 with the old vaccines has significantly degraded its infection prevention properties. Thankfully, protection against severe disease remains. In order to improve the performance of vaccines, especially against infection prevention, updated vaccines containing material from variants of concern are needed.

The UK recently granted authorization for an updated version of the Moderna vaccine. The updated vaccine contains mRNA from the ancestral SARS-CoV-2 virus in the original Moderna vaccine as well as mRNA from the Omicron variant B.1.1.529. In recent clinical trials, this updated vaccine when used as a booster elicited better neutralizing antibody immune responses against Omicron as well as the all the previous variants of concern. It is likely this will translate into better infection protection against BA.5, although it is uncertain whether it will improve on existing protection against severe disease as well.

Nevertheless, many Covid-19 vaccine makers are updating their vaccines. There is a race against time aspect where SARS-CoV-2 may further mutate by the time the updated vaccines are available and blunt the impact of the new formulations. The strategy of using bivalent and even multivalent vaccines will ensure at least some cross-protection. The question then becomes how often these updated boosters will need to be given. If protection against severe disease is maintained at current levels, updated boosters will likely only need to be given once a year, if not less often.

In summary, there is little chance that vaccine efficacy against severe disease will be significantly degraded by emerging variants to the point where we are back to square one of the pandemic. Even fully vaccinated but unboosted individuals retain some significant protection against severe disease. At least one booster mitigates waning antibody levels and tops off protection from severe disease. A second booster is advisable for vulnerable populations. Updated vaccines are on the way and will ensure we can neutralize future variants. In the meantime, using measures such as continued masking and public health standards help keep emerging variants under control and keep the maximum number of people safe.