How Do We Know Whether A Covid-19 Vaccine Is Effective?
Covid-19 vaccine bottle and syringe. getty  As new strains of Coronavirus emerge, we need to know whether existing vaccines are effective against variants. But while "Does this Covid-19 vaccine work?" seems like a simple question, it's actually challenging to answer. Although news headlines proclaiming that a vaccine is effective aren't exactly misleading, they do oversimplify the situation, and it's important for the public to understand what journalists and even scientists mean by the word "effective". Broadly speaking, we can define the effectiveness or 'efficacy' of a vaccine in two ways: according to how well it works at: 1) Generating immune responses; or 2) Achieving clinical 'endpoints'. 1. Immune Responses  The first definition of effective is based on a vaccine's ability to generate immune responses, known as 'immunogenicity'. One such response is for a drug to prompt your immune system to make antibodies. Vaccines work by exposing you to a specific antigen  usually a viral protein  so your defences learn to recognize it in advance and later generate antibodies that neutralize any virus carrying the antigen. In a Covid vaccine, the antigen is the spike protein that a SARS-CoV-2 virus uses to invade a human cell via a surface receptor called ACE2 (mRNA vaccines deliver genes so that your body produces the spikes itself). Antibodies attach to matching antigens on the surface of a virus particle, which will neutralize it in various ways  such as physically blocking the virus from docking with a cell or marking the invader for destruction. Neutralizing antibody response to Coronavirus spikes. CC BY-SA 4.0 xspareta / Wikimedia  Evolution can cause changes in the Coronavirus spike antigen so that a variant's spikes no longer match the specific antibodies generated through vaccination. One way to assess a vaccine's efficacy then is to measure the level of antibody that's required to neutralize viruses in a laboratory. Such experiments involve taking antibodies from the blood serum of vaccinated people and adding more and more of a virus to see how well the antibodies attach. Several studies have shown that current vaccines are effective against variants in terms of neutralisation, as highlighted by two recent papers published in the journal Nature. In one study, antibodies from 20 vaccinated people who had received Johnson & Johnson/Janssen's drug (Ad26.COV2.S) were able to bind the original Coronavirus and the 'Variant of Concern' Alpha (B.1.1.7) to about the same degree, although those antibodies were almost three times less efficient at binding two other variants of concern, Beta (B.1.351) and Gamma (P.1). The other study, on people who were given Pfizer/BioNTech's vaccine (BNT162b2), showed that antibodies from their serum samples could neutralize the Delta variant (B.1.617.2). Neutralizing antibodies aren't the only way to measure immunogenicity, however, as vaccines prompt other parts of the immune system to respond to antigens too. Most notably, T cells also learn to recognize antigens and can rapidly multiply to destroy infected cells  and as the Johnson & Johnson study found, "T cell responses were largely preserved against SARS-CoV-2 variants." But as the Pfizer paper points out, measuring immune responses via experiments such as neutralisation tests "cannot substitute for studies of vaccine efficacy and real-world effectiveness of COVID-19 vaccines against variants." 2. Clinical Endpoints  The goal of vaccine development is to manufacture a drug that's effective at protecting people, and so a vaccine's effectiveness can also be defined by its ability to achieve desired clinical outcomes or 'endpoints'. As explained by a review in The Lancet, an endpoint could be chosen at any one of many steps for healthcare, including preventing infection, disease, hospital admission or death. Potential endpoints for an effective Covid-19 vaccine. Hodgson et al (2021) The Lancet Infectious Diseases 21: E26-E3 / Elsevier  With the efficacy of Covid vaccines, the endpoint that's often highlighted in scientific papers and mainstream press is effectiveness at preventing moderate to severe disease. The data used to calculate that figure comes from observing people to get the proportion of individuals who were protected by vaccination. For such observational studies, the gold standard would be a randomized control trial, in which vaccinated volunteers are compared to unvaccinated participants. But with an ongoing pandemic and emergence of new variants, such trials can take too long and could be considered unethical for those who don't receive a drug. A widely-used alternative is to assess efficacy after a vaccine starts getting distributed to the general population. Such post-roll out studies involve checking the vaccination status of those who develop (usually moderate to severe) disease, then multiplying the total by the proportion who were vaccinated. Unvaccinated people serve as a sort of control group for calculation, which produces a percentage for a vaccine's efficacy. Efficacy is often adjusted to give an overall figure for a population. Because different age groups are susceptible to Coronavirus to varying degrees  with the elderly being most vulnerable and children being least, for example  the number may be adjusted to account for variation in age. When several strains of a virus are circulating in the population, each person should also be tested for which variant caused their infection, which helps give a figure for effectiveness against a particular variant. The need to test people for variants is illustrated by a study in the New England Journal of Medicine, which found that Johnson & Johnson's vaccine was 66% effective in Brazil. Closer inspection, however, revealed that two distinct strains  the original virus and Zeta (P.2), a 'Variant of Interest'  were circulating at that time (31 versus 69%), which means the 66% figure didn't reflect effectiveness against the so-called "Brazilian variant", Gamma (P.1). Post-roll out research does have a major weakness: researchers can only measure a vaccine's efficacy against a particular variant when that strain is already circulating in the population. Ideally, we would want to predict a drug's effectiveness before a variant becomes widespread, which is why experiments like neutralisation tests remain useful. In fact, while measuring immune responses might not necessarily prove that a vaccine prevents Covid, a theoretical model in Nature Medicine suggests that levels of neutralizing antibodies are highly correlated with protection against symptomatic infection by SARS-CoV-2. All this means is there are currently more ways to assess if a Coronavirus vaccine is effective than there are variants of concern.