COVID-19 Data Dives: A Biostatistician's Primer on Vaccine Efficacy

Natalie E. Dean, PhD


November 16, 2020

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Natalie E. Dean, PhD

As early results emerge from phase 3 COVID-19 vaccine efficacy trials, it is helpful to review the basics of how vaccines are evaluated. In that light, I offer a biostatistician's primer on vaccine efficacy. I'll refresh readers on the difference between vaccine efficacy and effectiveness, how to measure reduced infectiousness, and how to distinguish between efficacy against infection, disease, and severe disease.

Vaccine efficacy. Vaccine efficacy measures the relative reduction in disease for the vaccinated group vs the unvaccinated (placebo) group. A perfect vaccine would eliminate risk entirely and have a vaccine efficacy of 100%. 

This relative reduction can be calculated by one of three ways:

  • Using the risk ratio

  • Using the incidence rate ratio

  • Using the hazard ratio

A vaccine efficacy of 50% means the risk of the recipient becoming sick has been reduced by half when compared to an unvaccinated individual. To put it another way when explaining this to your patients, a vaccinated person has a 50% chance of becoming sick in the situation of exposure to the amount of infectious virus that would make an unvaccinated person sick.

Though we talk about vaccine efficacy as a single number, there are actually several different measures of vaccine efficacy, including:

  • Efficacy to prevent infection (sterilizing immunity)

  • Efficacy to prevent disease, including mild or moderate symptoms

  • Efficacy to prevent severe disease

In most phase 3 COVID-19 vaccine trials, the primary aim is to measure efficacy against disease of any severity. Measuring efficacy against infection and efficacy against severe disease is included as secondary analyses. The choice of primary endpoint reflects a balance of scientific and practical considerations.

The public health burden of interest is disease, particularly severe disease. As this pandemic has amply illustrated, severe disease occurs much less frequently than mild or moderate disease. To reliably estimate efficacy against severe disease, a trial would need to be much larger and run for longer.

In an ideal world, a vaccine would prevent infection entirely and, it follows, also prevent disease and severe disease. But this may be hard to achieve for a respiratory virus vaccine. Animal challenge data suggest that vaccinated animals may still be infected even if they don't experience symptoms. A vaccine that is able to reduce the severity of disease, even if it cannot prevent infection entirely, would obviously still have enormous public health value. Therefore, this is what trials target as their primary aim.

Phase 3 efficacy trials focus on evaluating how well a vaccine directly protects the vaccinated individual. This is the basis for regulatory decisions about whether a vaccine should be approved for individual use.

In addition to protecting the individual, an important vaccine effect is the ability of a vaccine to reduce infectiousness to others. This indirect protection is related to the concept of herd immunity. If I can't get infected, I can't infect you. Protect enough people and the virus will lack susceptible hosts, thus preventing a new outbreak.

But if a vaccinated person does become infected, even if they lack symptoms, it is possible for them to still be infectious to others. In that case, another way vaccines can provide indirect protection is by reducing viral shedding and the duration of infectiousness, making transmission less likely.

Beyond measuring viral shedding in infected participants, as some phase 3 trials are doing, we can directly observe reduced infectiousness through the use of add-on household studies. Following the household contacts of infected vaccinated and unvaccinated individuals allows for a comparison of infections in the household contacts of both. This can provide an important source of data for calculating how many people will need to be vaccinated to reduce transmission enough to control the virus.

Vaccine effectiveness. It is helpful to understand the difference between vaccine efficacy and vaccine effectiveness. The terms "efficacy" and "efficacious" are typically reserved for estimates from well-controlled, randomized trials where everyone receives the vaccine as intended (proper cold chain, all doses received on the correct schedule). This idealized estimate can be viewed as an upper bound for how well the vaccine can work in perfect circumstances.

In practice, though, circumstances may not be perfect when we roll out a vaccine. Protection of the vaccine in the real world is the true measure of "effectiveness." While conceptually we think of efficacy as inherent to the vaccine, effectiveness can — and will — vary from setting to setting. And this will be the best measure of whether these vaccines will truly be the breakthrough we all await.

Natalie Dean, PhD, is an assistant professor of biostatistics at the University of Florida in Gainesville. She specializes in emerging infectious diseases and vaccine study design. Follow her on Twitter

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