Waxing Understanding of Waning Immunity.

Of the approximately 150 000 deaths due to rotavirus infection that occur globally every year, >90% are among children in settings of low and low/middle incomes [1, 2]. To counter this burden, the World Health Organization recommends that rotavirus vaccination be included in the immunization program of all countries. Despite the clear signs of progress in reducing the rotavirus disease burden globally [3], there are 2 related challenges specific to lower-income settings that hamper rotavirus vaccines from preventing more deaths and severe diarrheal disease [4]. First, rotavirus vaccines are less effective in low-income as compared to high-income settings. This is, at least in part, an immunological phenomenon. Vaccine responses are considerably more robust among children in high-income settings as compared to low-income settings [5]. Second, vaccine protection appears to wane. Again, this issue appears to be restricted to low-income settings, where vaccine efficacy (VE) has been observed to drop 30%–40% from the first to second year of life in clinical trials in Kenya, Mali, Malawi, Ghana, South Africa, and Bangladesh [6–10]. Contrast this finding to that in Finland, for example, where a VE of >90% persists through the first 5 years of life [11]. Of course, it is not a country’s economic standing per se that compromises vaccine performance. Instead, low income is a proxy for other factors that may either reduce the titer of vaccine reaching the infant’s gut, such as maternal antibodies, or inhibit the child’s immune response, such as chronic inflammation or coinfection [4]. Similar factors are hypothesized to explain the decline in vaccine protection as children age. Lower antibody titers mounted in response to vaccination more quickly fall below protective levels, although for rotavirus it is not entirely clear what constitutes a protective threshold [12]. These factors may seem a logical explanation for the variable and waning VE measured in rotavirus clinical trials and waning vaccine effectiveness measured in observational studies. Rogawski et al, in the current issue of The Journal of Infectious Diseases, offer another explanation [13]. Perhaps lower and declining VE in low-income settings is not due to an ebbing of antibodies or other correlate of protection, but rather can be explained, at least in part, by a fundamental flaw in how we conceptualize and measure VE. In clinical trials and observational cohort studies, VE and vaccine effectiveness are measured by comparing the differential risks, rates, or hazards of disease in vaccinated groups to those in unvaccinated groups. If the groups are similarly exposed to infection (a safe assumption under randomization), rates of disease are lower among those receiving an efficacious vaccine. However, for so-called leaky vaccines that only provide partial protection to vaccinated individuals, unvaccinated individuals are infected at a higher rate and thus disproportionately acquire immunity naturally over time. In this sense, the unvaccinated individuals become more like the vaccinated individuals as they age and are exposed to infection. Therefore, if we calculate VE on the basis of the risks (ie, number of cases in the vaccinated and unvaccinated groups), it will be biased downward and appear to decline over time. Importantly, there is no waning of immunity in the immunological sense assumed in this scenario, but a biased estimate results. This biased estimator is readily overcome by analyzing instantaneous incidence or hazards. In other words, one must only analyze the rates among those who have not yet had an episode prior to a given time point. This phenomenon was pointed out >30 years ago by Smith et al [14], but it has been applied primarily to infections that confer sterilizing immunity (eg, measles), such that individuals once vaccinated or infected become immune to future infections, as well as disease. However, rotavirus infection, as with many enteric, respiratory, and genitourinary infections of mucosal surfaces, does not confer sterilizing immunity. This means that previously infected individuals get reinfected, just at lower rates and/or with milder disease. Rogawski et al extend Smith et al’s insights to rotavirus infection, an imperfectly immunizing infection, using data from the PROVIDE study [13]. PROVIDE was a randomized controlled trial conducted in Dhaka, Bangladesh, in which 700 children were assigned to receive either monovalent rotavirus vaccine (RV1) at 10 and 17 weeks of age or no RV1 E D I T O R I A L C O M M E N T A R Y