The vast majority of vaccines are prophylactic in nature. As a result, the demonstration of their efficacy paradoxically requires the infectious disease to occur among non-diseased study participants randomized between investigational vaccine and appropriate control groups. The statistics of vaccine efficacy (VE) calculation are nearly entirely and solely based on the number of observed incident disease cases during follow-up. For certain diseases, the sample sizes needed to achieve the required number of observations may reach 5,000 subjects or many more, requiring vaccine mega-trials to be conducted. In this article, the author provides an overview of mega vaccine trials conducted over the last 20 years.
Prophylactic vaccines generally are intended for healthy or medically stable populations. Administration to hundreds of thousands or even millions of people in a few years after licensure is not exceptional. The immune responses induced by candidate vaccines are extensively characterized during Phase II with natural infection serving as a benchmark. However, a correlate of protection is often not established, at least not timely or sufficiently robustly as to support licensure. As a result, the preventative efficacy needs to be demonstrated clinically, as opposed to only “immunologically.” This is reflected in the prelicensure requirements of regulatory authorities in the U.S., Europe and other major geographies. A recent exception is the meningococcal B vaccine (Bexsero®) for which a robust and well-accepted immunological correlate of protection was used as a surrogate for clinical efficacy. Conducting a vaccine efficacy (VE) trial would have required a prohibitively large sample size given the very low disease incidence. Another example is the Vaxchora® cholera vaccine, which was registered by the U.S. Food and Drug Administration based on a controlled human infection model that demonstrated efficacy with a very modest sample size of approximately 100 participants.
The prophylactic effect of vaccines, as opposed to therapeutics, requires randomized well-controlled clinical efficacy trials to be large in sample size and lengthy in follow-up time to allow incident disease events to accrue. Paradoxically, the disease intended to be prevented needs to occur in sufficient numbers to allow statistical demonstration of efficacy. The control group is either a placebo (absolute efficacy) or an established active comparator (relative efficacy, vaccine efficacy increase). The target disease’s incidence rate may be as small as 1% per annum or even lower, driving the sample size upwards. Additionally, sponsors may be required to demonstrate lower limits of VE greater than zero, further leading to very large sample sizes, long follow-up times or both.
This survey of the literature focuses on “mega-trials,” defined as Phase III clinical studies assessing VE with a sample size of 5,000 participants or more that were published since 2000. Only the first publication of each Phase III study, some interim, has been retained for this descriptive summary of trials. To complement this review, the same literature search was performed for the publication period from 1980 to 1999.
For the publication period starting in 2000 a PubMed search retrieved more than 1,000 articles, which after review allowed the selection of 53 unique VE Phase III studies of 5,000 participants or more. Three Phase III trials even enrolled more than 100,000 subjects to assess vaccines against typhoid fever, cholera and hepatitis E. For the period from 1980 to 1999, 21 mega-trials were found using the same search and selection. The first such publication dates back to 1980 and reports the efficacy of a cholera vaccine among 202,136 participants in a study conducted in Calcutta. For the studies published before 2000, all studies except one (hepatitis A) are addressing bacterial diseases. This is in contrast with the period after 2000 when most trials aimed at viral diseases, with only a few targeting bacterial diseases and only one a parasitic disease.
Several prophylactic vaccines aimed at preventing a dozen different pathogen types have been tested in large randomized Phase III mega-trials to assess clinical efficacy before licensure. Most were viral vaccines; only one takes aim at a parasitic disease.
For the period in scope, the study start year and sample size are represented in Figure 1. For the period considered, the first mega-trials assessed vaccines targeting bacterial diseases: cholera, typhoid fever and invasive pneumococcal disease. Gradually, over the 20-year period, viral vaccines became dominant in the number of trials. This likely reflects progress made in antigen characterization and molecular biology. There was only one mega-trial of a parasitic vaccine, malaria.
The first mega-trials for viral vaccines were conducted for the rotavirus vaccines by Merck in 2001 and GSK in 2003, each study enrolled more than 60,000 participants. These large sample sizes were required to assess efficacy in addition to the potential risk of intussusception. This rare but serious event caused withdrawal of the Wyeth rotavirus vaccine a few years before.
With the primary objectives being the assessment of preventive efficacy against clinically overt, symptomatic infectious diseases, the incidence of primary efficacy endpoints is relatively low. These often range from a few cases per 1,000 participants to a few cases per 100 participants over the selected follow-up durations, which may vary from several weeks to several years. As a consequence large sample sizes and/or long follow-up durations are needed.
An unexpected and unplanned exception to low event rates was observed in a malaria vaccine Phase III study where the primary event rate of clinical malaria in the control group over the initial follow-up period was as high as 117% per year in children and 92% per year in young infants – one order of magnitude higher than the protocol estimates of 10% per annum, which were overly conservative.
Most trials used a placebo comparator and only few mega-trials used an active control vaccine, i.e., providing protection against another disease. This most often was required when established vaccines and recommendations existed in the same population. In the present review, only three influenza vaccine mega-trials used another influenza vaccine as a comparator. The major impact is an increase in the sample size. First, because the relative VE is smaller than the absolute VE in placebo-controlled trials. Second, because the overall event rate decreases significantly in both vaccinated groups.
Due to the massive clinical research efforts for COVID-19 vaccines, over approximately a two-year time period an unprecedented uptick in the number of mega vaccine trials performed was observed. Twenty-one published placebo-controlled mega-trials of several COVID-19 vaccines have enrolled over 560,000 participants in about two years’ time. This is quite remarkable compared to the 2009 H1N1 influenza pandemic where not one mega-trial was conducted for licensure, and mostly driven by the scientific need to assess both efficacy and safety of novel vaccine technologies against a new pathogen. In contrast, the H1N1 pandemic vaccines used established influenza vaccine technologies against a well-known pathogen for which a correlate of protection existed.
Mega-trials – enrolling 5,000 participants or more to demonstrate clinical efficacy of prophylactic vaccines – are rare in comparison with the large number of interventional vaccine clinical trials that are conducted. These unique studies represent enormous operational efforts to be conducted and very large financial investments, often in the range of several hundreds of millions of U.S. dollars. Despite their huge sample size, nearly the entire value and information is concentrated in the fairly small number of primary endpoints of confirmed diagnoses of the target disease. Capturing these efficacy endpoints requires significant effort and focused attention and only can be successfully achieved by the combination of highly cooperative participants, skilled investigators and dedicated staff, and operationally savvy clinical research operations.
Paul Gillard, M.D., vice president, medical science & strategy, vaccines therapeutic area, PPD clinical research business, Thermo Fisher Scientific
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