Non-specific effect of vaccines

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 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.