Non-specific effects of vaccines (also called "heterologous effects" or "off-target effects") are effects which go beyond the specific protective effects against the targeted diseases. Non-specific effects from live vaccines can be strongly beneficial by increasing protection against non-targeted infections. This has been shown with childhood mortality in two live attenuated vaccines, BCG vaccine and measles vaccine, through multiple randomized controlled trials. Non-specific effects of non-live vaccination may be detrimental, increasing overall mortality at least 30% by some estimates, despite providing protection against the target disease. Observational studies suggest that diphtheria-tetanus-pertussis vaccine (DTP) may be highly detrimental, and although a WHO report described such studies as at high risk of bias, the direction of such bias was not predicted; although the conclusions have failed to replicate in some similar studies conducted by independent groups, randomized controlled trials (RCTs) provide additional evidence that vaccines have potent nonspecific effects.

Ongoing research suggests that non-specific effects of vaccines may depend on the vaccine, the vaccination sequence, and the sex of the infant. For example, one hypothesis suggests that all live attenuated vaccines reduce mortality more than explained by prevention of target infections, while all inactivated vaccines may increase overall mortality despite providing protection against the target disease. These effects may be long-lasting, at least up to the time point where a new type of vaccine is given. The non-specific effects can be very pronounced, with significant effects on overall mortality and morbidity. In a situation with herd immunity to the target disease, the non-specific effects can be more important for overall health than the specific vaccine effects.

The non-specific effects should not be confused with the side effects of vaccines (such as local reactions at the site of vaccination or general reactions such as fever, head ache or rash, which usually resolve within days to weeks – or in rare cases anaphylaxis). Rather, non-specific effects represent a form of general immunomodulation, with important consequences for the immune system's ability to handle subsequent challenges.

It is estimated that millions of child deaths in low income countries could be prevented every year if the non-specific effects of vaccines were taken into consideration in immunization programs. Although childhood mortality is an important metric, non-specific effects have also been observed for vaccination events and conditions that occur much later in life.

History

The hypothesis that vaccines have non-specific effects was formulated in the early 1990s by Peter Aaby at the Bandim Health Project in West Africa.

The first indication of the importance of the non-specific effects of vaccines came in a series of randomized controlled trials (RCTs) in the late 1980s. It was tested whether a high-titer (high concentration) measles vaccine (HTMV) given at 4–6 months of age was as effective against measles infection as the standard measles vaccine (MV) given at 9 months of age. Early administration of the HTMV prevented measles infection just as effectively as did the standard MV given at 9 months of age.

However, early administration of the HTMV was associated with twofold higher overall mortality among females (there was no difference in mortality for males). In other words, the girls given HTMV died more often despite having the same protection against measles as the infants given standard MV. The discovery forced WHO to withdraw the HTMV in 1992. It was later discovered that it was not the HTMV, but rather a subsequent inactivated vaccine (DTP or IPV for different children), that caused the increase in female mortality. Although the mechanism was different than initially thought, this finding represents unexpected effects of a change in the vaccine program not attributable to the disease-specific protection provided by the vaccines.

This first observation that vaccines could protect against the target disease but at the same time affect mortality after infection with other pathogens, in a sex-differential manner, led to several further studies showing that other vaccines might also have such nonspecific effects.

Live attenuated versus inactivated vaccines Numerous observational studies and randomised trials (RCTs) have found that the impact on mortality of live and inactivated vaccines differ markedly. All live vaccines studied so far (BCG, measles vaccine, oral polio vaccine (OPV) and smallpox vaccine) have been shown to reduce mortality more than can be explained by prevention of the targeted infection(s). In contrast, inactivated vaccines (diphtheria-tetanus-pertussis (DTP), hepatitis B, inactivated polio vaccine) may have deleterious effects in spite of providing target disease protection.

BCG vaccine The live attenuated BCG vaccine developed against tuberculosis has been shown to have strong beneficial effects on the ability to combat non-tuberculosis infections.

Several studies have suggested that BCG vaccination may reduce atopy, particularly when given early in life. Furthermore, in multiple observational studies BCG vaccination has been shown to provide beneficial effects on overall mortality. These observations encouraged randomised controlled trials to examine BCG vaccination's beneficial non-specific effects on overall health. Since BCG vaccination is recommended to be given at birth in countries that have a high incidence of tuberculosis it would have been unethical to randomize children into "BCG" vs. "no BCG" groups. However, many low-income countries delay BCG vaccination for low-birth-weight (LBW) infants; this offered the opportunity to directly test the effect of BCG on overall mortality.

In the first two randomised controlled trials receipt of BCG+OPV at birth vs. OPV only ('delayed BCG') was associated with strong reductions in neonatal mortality; these effects were seen as early as 3 days after vaccination. BCG protected against sepsis as well as respiratory infections. Among BCG vaccinated children, those who develop a BCG scar or a positive skin test (TST) are less likely to develop sepsis and exhibit an overall reduction in child mortality of around 50%.

In a recent WHO-commissioned review based on five clinical trials and nine observational studies, it was concluded that "the results indicated a beneficial effect of BCG on overall mortality in the first 6–12 months of life. Relevant follow-up in some of the trials was short, and all of the observational studies were regarded as being at risk of bias, so the confidence in the findings was rated as very low according to the GRADE criteria and "There was a suggestion that BCG vaccination may be more beneficial the earlier it is given". Furthermore, "estimated effects are in the region of a halving of mortality risk" and "any effect of BCG vaccine on all-cause mortality is not likely to be attributable to any great extent to fewer deaths from tuberculosis (i.e. to a specific effect of BCG vaccine against tuberculosis)". Based on the evidence, the WHO's Strategic Group of Experts on Immunization (SAGE) concluded that "the non-specific effects on all-cause mortality warrant further research".

Polio vaccine

The oral polio vaccine (OPV) was developed in the 1950s by Dr. Albert Sabin and is made from live attenuated polioviruses of three serotypes.Sabin, AB. Characteristics and genetic potentialities of experimentally produced and naturally occurring variants of poliomyelitis virus. Ann NY Acad Sci 1955; 61: 924-38. The first evidence of non-specific effects of OPV was protection by vaccination with OPV of serotype 2 against disease caused by serotype 1 poliovirus without any evidence of cross-neutralization.Hale, JH, Doraisingham, M, Kanagaratnam, K, Leong, KW, Monteiro, ES. Large-scale use of Sabin type 2 attenuated poliovirus vaccine in Singapore during a type 1 poliomyelitis epidemic. Br Med J 1959; 1(5137): 1541-9. Vaccination with trivalent OPV helped to stop outbreak of paralytic disease caused by Enterovirus 71 in Bulgaria.Shindarov, LM, Chumakov, MP, Voroshilova, MK, et al. Epidemiological, clinical, and pathomorphological characteristics of epidemic poliomyelitis-like disease caused by enterovirus 71. Journal of hygiene, epidemiology, microbiology, and immunology 1979; 23(3): 284-95. In large prospective clinical trials OPV was shown to protect against seasonal influenza and other acute respiratory diseases.Chumakov, MP, Voroshilova, MK, Antsupova, AS, et al. [Live enteroviral vaccines for the emergency nonspecific prevention of mass respiratory diseases during fall-winter epidemics of influenza and acute respiratory diseases]. Zh mikrobiol, epidemiol, immunobiol (in russian) 1992; (11-12): 37-40.Voroshilova, MK. Potential use of nonpathogenic enteroviruses for control of human disease. Prog Med Virol 1989; 36: 191-202. Immunization with OPV was also shown to lead to a faster healing of genital herpes lesions. Immunization with OPV was found to reduce all-cause childhood mortality Lund, N, Andersen, A, Hansen, AS, et al. The Effect of Oral Polio Vaccine at Birth on Infant Mortality: A Randomized Trial. Clin Infect Dis 2015; 61(10): 1504-11.Andersen, A, Fisker, AB, Rodrigues, A, et al. National Immunization Campaigns with Oral Polio Vaccine Reduce All-Cause Mortality: A Natural Experiment within Seven Randomized Trials. Front Public Health 2018; 6: 13. even in the absence of wild poliovirus circulation, hospital admission rate,Sorup, S, Stensballe, LG, Krause, TG, Aaby, P, Benn, CS, Ravn, H. Oral Polio Vaccination and Hospital Admissions With Non-Polio Infections in Denmark: Nationwide Retrospective Cohort Study. Open forum infectious diseases 2016; 3(1): ofv204. incidence of bacterial diarrhea,Upfill-Brown, A, Taniuchi, M, Platts-Mills, JA, et al. Nonspecific Effects of Oral Polio Vaccine on Diarrheal Burden and Etiology Among Bangladeshi Infants. Clin Infect Dis 2017; 65(3): 414-9. and otitis media.Seppala, E, Viskari, H, Hoppu, S, et al. Viral interference induced by live attenuated virus vaccine (OPV) can prevent otitis media. Vaccine 2011; 29(47): 8615-8. Vaccination with OPV results in Interferon induction that is believed to be the main mediator of the non-specific protective effects of OPV.

Measles vaccine

Standard titer measles vaccine is recommended at 9 months of age in low-income countries where measles infection is endemic and often fatal. Many observational studies have shown that measles-vaccinated children have substantially lower mortality than can be explained by the prevention of measles-related deaths. Many of these observational studies were natural experiments, such as studies comparing the mortality before and after the introduction of measles vaccine and other studies where logistical factors rather than maternal choice determined whether a child was vaccinated or not.