The Yin and Yang of the Non-Specific Effects of Vaccines

The Non-Specific Effects (NSE) of vaccines refers to any other effect of a given vaccine, other than the intended effect of reducing disease from the specific vaccination. This area of public health has received a large amount of attention in recent years, with arguments on both sides suggesting that vaccines have either beneficial or detrimental NSE. So, where did it all start, what does it all mean and how does the present study contribute to our understanding of this complex and emotive issue? Some of the first evidence of the NSE of vaccines came from a group in Guinea-Bissau studying the introduction of a high titer measles virus into the WHO's Expanded Programme on Immunization (EPI) vaccine schedule (Aaby et al., 1993a; Aaby et al., 1993c). The authors conducted a randomised controlled trial to determine if high titer measles virus (MV), given at 4–6 months, was as effective as the standard MV dose that was being routinely given at 9 months of age. It was, but subsequent studies noted that therewas a twofold highermortality rate in infants given the high titer MV vaccine, and that this effect was seen only in girls, and not boys (Aaby et al., 1993b). It is important to note that both of the MV vaccines are live, attenuated vaccines. Subsequent analysis (Aaby et al., 2003) suggested that the sex-specific mortality associated with high titer MV was due, not to the MV vaccine itself, but the later administration of non-live vaccines, such as the combination vaccine Diphtheria/Pertussis/Tetanus (DPT). Recently, the same group has reanalysed survival data from a more recently developed non-live vaccine, the anti-malarial vaccine, RTS,S (Klein et al., 2016). The data presented in this analysis would also suggest that if the last vaccine you are given is a non-live vaccine (DPT or RTS,S for example), then there is a higher mortality rate in females receiving these vaccines than if you were given a live vaccine as the last vaccine. There appears to be no deleterious NSE for any vaccine in males. But things are not as bad as they seem. The same group fromGuineaBissau has shown that if another live vaccine, BCG, is given at the time of birth to underweight babies, there is a significant decrease in all-cause mortality in the first four weeks of life (Aaby et al., 2011). Others have shown that BCG confers a non-specific benefit in adults given influenza vaccination (Leentjens et al., 2015), likely in a process known as “trained innate immunity” (Saeed et al., 2014). It is not currently clear how the deleterious effects of non-live vaccines interrupt the beneficial effects of live vaccines, butmore clearly needs to be done to understand these phenomena.