An Expert Explains: Why vaccine efficacy is declining, and the implications of a third dose

Is this a cause for alarm?

No, because protection against hospitalisation is still high. Ideally, a public vaccination programme should protect the population from infection, transmission, and hospitalisation (and subsequent mortality). Initial vaccine efficacy data showed high efficacy versus infection and hospitalisation. (The correlation between infection and transmission is not automatic and has to be proven. Some post-clinical trial data showed this for the current vaccines.) Even if protection against infection decreases, vaccines highly protective against hospitalisation are still beneficial because hospitalisations place the maximum burden on healthcare capacity. As long as the disease can be managed at home (and there are no lingering effects such as long Covid) then is it any worse than flu-like discomfort?

The data do show that protection versus hospitalisation remains high. The recent disease trends in the UK provide additional support. Recently, cases there reached up to 85% of the prior peak in January 2021 whereas the number of deaths stayed at 10% of the prior peak.

Any concerns about the numbers being in the 70s and 80s versus the initial high 90s are countered by two observations. One is that the initial efficacy numbers were based on few months’ data from trials in a highly controlled setting. Real-world data tend to be lower. Furthermore, there are confidence intervals around these averages that make any concrete conclusion about a true decline in effectiveness difficult.

What could be the explanation for the differences in effectiveness?

The statement “The immune system is incredibly complex” is a woefully minimal description of the intricate set of interconnected reactions collectively called the immune system that protects us from disease-causing agents. The explanation below is a basic outline, and as with any simplification some inaccuracies creep in, but these do not distort the overall message.

The virus, as it ‘infects’ the body, is primarily found in two locations. One is the circulation system that it uses to travel around the body. The second is the cells of various tissues that the virus invades and uses to multiply. Logically, therefore, the immune system has two main ‘arms’ to confront the virus in these two locations. One is the antibody arm. Antibodies ‘lock in’ on certain surface proteins of the circulating virus, thereby preventing it from invading our cells. Further, they ‘tag’ the virus for destruction. Thus, antibodies can be thought as a first line of defence, but they become ineffective once the virus enters the cells. At this point, the second arm of the immune response becomes relevant.

This arm is aptly named the Killer T cell arm. These cells target our own bodies’ cells that harbour the virus and within which the virus replicates. The T cells kill such cells, thereby eliminating the virus within them. Proceeding with a simplistic view that disease is caused once the virus takes hold in our bodies’ cells, a strong T-cell immune function can protect from severe disease even if the antibody response is weak.

Vaccination establishes the two arms of the immune response; these two arms can mature differently with time and in response to variants. Circulating antibody levels decline with time. Even though there is “memory” in the system to produce antibodies on-demand, jumpstarting this memory at a subsequent encounter can take time. A weak and delayed antibody response would result in an infection (symptomatic Covid), but if the T-cell response is intact, the individual would be protected from severe disease.

Additionally, vaccine effectiveness can reduce because the immune system that has been primed by one variant has to counter a new variant. Even here, the differences in response of the two arms to a variant are crucial. The antibody arm reacts to the viral surface proteins (primarily the shape, or the 3D configuration), and thus changes in this surface protein can reduce the effectiveness of the antibody response. The T cells, however, react to smaller fragments of the surface and other viral proteins. Since the T cells respond to a broader set of targets — more proteins (surface and non-surface) and more sites on the proteins (multiple fragments) as compared to antibodies that respond to a specific site (or sites) on the surface protein controlled by the local “shape” at the site, the T-cell response can be more resistant to variants.

So, the table can be explained by a decline in antibody effectiveness caused by time and variants that reduces VE versus symptomatic disease. Continuing effectiveness of the T-cell response explains the ongoing protection against hospitalisation. An important note is that at present, this explanation is conjecture based on the general principles of immune system function. Recent studies tracking a few individuals have reported that the T-cell response to Covid vaccines is durable and effective versus the variants. More data will be required to confirm and perfect the above basic explanation.

The simplified picture also indicates that circulating antibodies are not the entirety of the available protective resources. Antibody tests are easier to implement at large scale as compared to T-cell measurements and are therefore widely available. Individuals, however, should not base lifestyle decisions on such tests. The best practice is to get vaccinated and follow the local guidance on appropriate behaviour.

Will a third dose help?

Given that a two-dose regimen is still highly protective against hospitalisation, the principal benefit of a third dose would be in improving effectiveness versus infection. Current limited data shows improvement in antibody levels and increase in effectiveness after a third dose. Consequently, some countries are considering a targeted roll-out of the third dose – in high-risk populations.

Nevertheless, there are other questions to consider. Since the vaccine is still based on the original ‘Wuhan strain’, the longer-term effectiveness is one concern. If immunity wanes after two doses, how long will the third dose remain effective? Will it protect against potential new variants? Another vital topic, especially in a resource-constrained situation, is the balance between reducing infection in an already vaccinated population via a third dose weighed against denying a first or second dose – one that protects from hospitalisation – to the partially or completely unvaccinated. An imperfect analogy is the choice between giving a lifejacket to an individual already wearing one versus to a person without one. The analogy also highlights the conflicting interests of the individual versus the collective.

In India, the majority of the population is not fully vaccinated and is therefore susceptible to hospitalisation. Furthermore, there is no data in the Indian population assessing possible reduction in two-dose effectiveness and benefits of a third. With such lingering questions and continued vaccine supply constraints, the priority should remain full vaccination of the eligible population (including approval of a vaccine for children) to control hospitalisation. The basic precautions to control the spread such as masking, distancing, basic hygiene, and ensuring appropriate ventilation in crowded indoor spaces should continue.

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