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Introduction
"Non-specific effect 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 can be strongly beneficial, increasing protection against non-targeted infections, but also at times negative, increasing susceptibility to non-targeted infections. This depends on both the vaccine and the sex of the infant.

All live attenuated vaccines studied so far (BCG vaccine, measles vaccine, oral polio vaccine, smallpox vaccine) have been shown to reduce mortality more than can be explained by prevention of the targeted infections. In contrast, inactivated vaccines (diphtheria-tetanus-pertussis (DTP), hepatitis B vaccine, inactivated polio vaccine) may have deleterious effects in spite of providing target disease protection.

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 thus not be confused with the commonly acknowledged side effects after vaccination (local reactions at the side of vaccination, general reactions such as fever, head ache or rash, which usually resolve within days/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.

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 non-specific effects came in a series of randomized controlled trials (RCTs) in the late 1980s. It was tested whether a high-titer measles vaccine (HTMV) could be given at 4–6 months of age and could be 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, at the same time 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 of being equally protected against measles as the infants given standard MV. The discovery forced WHO to withdraw the HTMV in 1992.

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) ans 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 already 3 days after vaccination. BCG protected specifically 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 concluded that “the non-specific effects on all-cause mortality warrant further research”.

Measles vaccine
There is considerable evidence that measles vaccine is associated with more survival benefits than expected based on the specific protection. No study contradicts these observations by showing that measles vaccine only protects against measles infection and measles death. To date, these observations have not been pursued, partly due to the absence of a mechanistic understanding.

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, for reviews, see. 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 it was logistical factors rather than maternal choice that determined whether a child was vaccinated or not.

These findings were later supported in randomized trials from 2003 to 2009 in Guinea-Bissau. An intervention group of children given standard titer measles vaccine at 4.5 and 9 month of age had a 30 % reduction in all-cause mortality compared to the children in the control group, which were only vaccinated against measles at 9 month of age.

In a recent WHO-commissioned review based on four randomized trials and 18 observational studies, it was concluded that ”There was consistent evidence of a beneficial effect of measles vaccine, although all observational studies were assessed as being at risk of bias and the GRADE rating was of low confidence. There was an apparent difference between the effect in girls and boys, with girls benefitting more from measles vaccination”, and furthermore ”estimated effects are in the region of a halving of mortality risk” and ”if these effects are real then they are not fully explained by deaths that were established as due to measles”. Based on the evidence, the WHO’s Strategic Advisory Group of Experts on Immunization concluded that "the non-specific effects on all-cause mortality warrant further research”.

Diphtheria-tetanus-pertussis vaccine
DTP vaccine against diphtheria, tetanus and pertussis does not seem to have the same beneficial effects as BCG, measles vaccine, OPV and smallpox vaccine, and in fact opposite effects are observed. The negative effects are seen as long as DTP vaccine is the most recent vaccine. BCG or measles vaccine given after DTP reverses the negative effects of DTP. The negative effects are seen mostly in females.

The negative effects are found in several observational studies. However, six WHO-commissioned studies concluded that there were strong beneficial effects of DTP on overall mortality. However, [controversy] ensued as to the design of these studies that had important methodological shortcomings. Among others, the WHO-commissioned studies had counted “no information about vaccination” as “unvaccinated”, and they had retrospectively updated vaccine information from surviving children, while no similar update could be made for dead children, creating a so-called “survival bias” which will always produce highly beneficial effect estimates for the most recent vaccine.

As all the studies of the overall mortality effect of DTP vaccine are observational studies, they are probably prone to selection bias, but this selection bias would tend to work in favor of vaccinated children, and therefore the consistent observation of negative effects in studies without survival bias is worrying.

In a recent WHO-commissioned review of DTP based on ten observational studies, it was concluded that, ”[t]he findings were inconsistent, with a majority of the studies indicating a detrimental effect of DTP, and two studies indicating a beneficial effect. All of the 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.”

Furthermore ”three observational studies provided a suggestion that simultaneous administration of BCG and DTP may be preferable to the recommended schedule of BCG before DTP; and there was suggestion that mortality risk may be higher when DTP is given with, or after, measles vaccine compared with when it is given before measles vaccine (from five, and three, observational studies, respectively). These results are consistent with hypotheses that DTP vaccine may have detrimental effects on mortality, although a majority of the evidence was generated by a group centred in Guinea-Bissau who have often written in defence of such a hypothesis.”.

Smallpox vaccine
Already when smallpox vaccine was introduced in the early 19s century, there were anecdotal descriptions of non-specific beneficial effects. In the second half of the 20th century the potential for beneficial non-specific effects of smallpox vaccine was reviewed, and new evidence on “para-immune effects” was added. More recent studies have focused on the phasing out of smallpox vaccine in the 1970s and compared vaccinated and unvaccinated cohorts. Smallpox vaccine leaves a very characteristic scar. In low-income countries, having a smallpox vaccine scar has been associated with reductions of more than 40% in overall mortality among adults ; in high-income countries smallpox vaccination has been associated with a tendency for reduced risk of asthma, and significantly reduced risk of malignant melanoma and infectious disease hospitalizations. There are no studies that contradict these observations. However it should be noted that no randomized trials testing the effect of smallpox vaccine on overall mortality and morbidity have been conducted.

Sex differences
Non-specific effects are frequently sex-differential. There are accumulating data illustrating that males and females may respond differently to vaccination, both in terms of the quality and quantity of the immune response. If true, then we must consider whether vaccination schedules should differ for males and females, or as has been suggested “should we treat the sexes differently in order to treat them equally?”

Interactions between health interventions
The non-specific effects of vaccines can be boosted or diminished when other immunomodulating health interventions like other vaccines, or vitamins, are provided.

Influence of pre-existing specific immunity
The beneficial NSEs of live vaccines are stronger with earlier vaccination, possibly due to maternal antibodies. Boosting with live vaccines also seems to enhance the beneficial effects.

High-income countries
The non-specific effects were primarily observed in low-income countries with high infectious disease burden, but they may not be limited to these areas. Recent Danish register-based studies have shown that the live attenuated measles-mumps-rubella vaccine (MMR) protects against hospital admissions with infectious diseases and specifically getting ill by respiratory syncytial virus.

Immunological mechanisms
The findings from the epidemiological studies on non-specific effects pose a challenge to the current understanding of vaccines, and how they affect the immune system, and furthermore question whether boys and girls have identical immune systems and should receive the same treatment.

The mechanisms by which the encounter with a vaccine can induce rapid changes in the general susceptibility to infectious diseases, effects which can lead to improved clearance of subsequent unrelated pathogens, but also at times lead to increased morbidity are unknown, but are likely to involve at least the following mechanisms.

Heterologous T-cell immunity
It is well known from animal studies that infections, apart from inducing pathogen-specific T-cells, also induce cross-reactive T-cells through epitope sharing, so-called heterologous immunity. Heterologous T-cell immunity can lead to improved clearance of a subsequent cross-reactive challenge, but it may also lead to increased morbidity. Hence, importantly, this mechanism holds the potential to explain how DTP could have negative effects.

It would, however, not explain effects occurring shortly after vaccine receipt, as for instance the rapidly occurring beneficial effects of BCG vaccine, as the heterologous effect would only be expected to be present after some weeks, as the adaptive immune response need time to develop. Also, it is difficult to explain why the effect would vanish once a child receives a new vaccine.

Trained innate immunity
The concept that not only plants and insects, but also humans have innate memory may provide new clues to why vaccines have non-specific effects. Studies into BCG have recently revealed that in adults, BCG induces epigenetic changes in the monocytes, leading to increased pro-inflammatory cytokine production upon challenges with unrelated mitogens and pathogens.

In SCID mice without an adaptive immune system, this translated into reduced mortality from otherwise lethal candida infection. The effects of BCG were seen after 2 weeks, but would be expected to occur rapidly after vaccination, and hence might be able to explain the very rapid protection against neonatal septicaemia seen after BCG vaccine.

Trained innate immunity may also explain the generally increased resistance against broad disease categories, such as fevers and lower respiratory tract infections; such effects would be difficult to explain merely by shared epitopes, unless such epitopes were almost universally common on pathogens.

Lastly, it is plausible that the effects are reversible by a new different vaccine. Hence, the exciting new research within the field of trained innate immunity seems promising in terms of being able to provide a biological mechanism for the observed non-specific effects of vaccines.

Controversy
In 2000 Aaby and colleagues presented data from Guinea-Bissau which suggested that DTP vaccination could, under some circumstances (e.g. absence of pertussis) be associated with increases in overall mortality, at least until children received measles. In response, WHO sponsored the analysis of a variety of data sets in other populations to test the hypothesis. None of these studies replicated the observation of increased mortality associated with DTP vaccination. WHO subsequently concluded, that the evidence was sufficient to reject the hypothesis for an increased nonspecific mortality following DTP vaccination.

However, Aaby and colleagues subsequently pointed out that the studies which failed to show any mortality increase associated with DTP vaccination used methods of analysis that can introduce a bias against finding such an effect.

In these studies, data on childhood vaccinations were typically collected in periodic surveys, and the information on vaccinations, which occurred between successive home visits, was updated at the time of the second visit. The person-time at risk in unvaccinated and vaccinated states was then divided up according to the date of vaccination during the time interval between visits. This method opens up a potential bias, insofar as the updating of person time at risk from unvaccinated to vaccinated is only possible for children who survive to the second follow-up. Those who die between visits typically do not have vaccinations between the first visit and death recorded, and thus they will tend to be allocated as deaths in unvaccinated children – thus incorrectly inflating the mortality rate among unvaccinated children.

This bias has been described before, but in different contexts, as the distinction between ‘landmark’ and ‘retrospective updating’ analysis of cohort data. The retrospective updating method can lead to a considerable bias in vaccine studies, biasing observed mortality rate ratios towards zero, whereas the landmark method leads to a non-specific misclassification and biases the rate ratio towards unity.

An additional problem with the literature on nonspecific effects of vaccines has been the variety and unexpected nature of the hypotheses which have appeared (in particular relating to sex-specific effects), which has meant that it has not always been clear whether some apparent ‘effects’ were the result of post hoc analyses or whether they were reflections of a priori hypotheses.

This was discussed at length at a review of the work of Aaby and his colleagues in Copenhagen in 2005. The review was convened by the Danish National Research Foundation and the Novo Nordisk Foundation who have sponsored much of the work of Aaby and his colleagues. An outcome of the review was the explicit formulation of a series of testable hypotheses, agreed by the Aaby group. It was hoped independent investigators will design and conduct studies powered to confirm or refute these hypotheses.

Also, the two foundations sponsored a workshop on analysis of vaccine effects, which was held in London in 2008. The workshop resulted in three papers. The proceedings were forwarded to WHO which subsequently concluded that it would “keep a watch on the evidence of nonspecific effects of vaccination”.

In 2013, WHO established a working group tasked with reviewing the evidence for non-specific effects of BCG, measles and DTP vaccine. Two independent reviews were conducted, an immunological review and an epidemiological review. The results were presented at the April 2014 meeting of WHO’s Strategic Gourp of Experts on Immunizations (SAGE). WHO/SAGE concluded that further research into the potential NSEs of vaccines was warranted.

Implications for world health
It would have major consequences for child survival if the non-specific effects of vaccines were taken into consideration in immunization programs: BCG and MV should be given to all children as early as possible; restrictive policies for opening multi-dose vials of BCG and MV should be abandoned.

Contrary to current WHO-recommendations the age of MV should not be raised when measles infection is under control; DTP should not be given simultaneously with MV or after MV and a booster dose of DTP is likely to have a negative effect on child survival. Finally, eradicating a disease and stopping a live vaccine with beneficial NSEs is likely to have negative effects for the overall health of the affected population.

Dr. Frank Shann from Australia recently assessed the consequences of changing the current EPI schedule to an alternative schedule taking non-specific effects into account, and concluded: “If all neonates in high-mortality regions were given BCG at birth, and the revised immunization schedule ... were adopted, with extra doses of measles vaccine at 14 weeks and 19 months (at a cost of only US $0.60/dose delivered), ~1 million (30%) of the 3.2 million neonatal deaths each year might be prevented in developing countries, and 1.5 million (30%) of the 4.8 million deaths between 1 month and 5 years of age might be prevented”. Furthermore: ”This very large reduction in mortality in children <5 years of age would be achieved at a low cost using only vaccines that are already in the routine EPI schedule”.

The Arc of the Swallow
In 2008, Danish crime novel author Sissel-Jo Gazan (author of the Danish crime novel of the decade, Dinosaur Feather) got interested in the work of the Bandim Health Project and based her scientific crime novel ”The Arc of the Swallow” (”Svalens Graf”) on the research into non-specific effects of vaccines.

In a completely fictional way, she basically asks the question whether anybody would kill a professor, who claimed that vaccine have non-specific effects.

The novel was published in Danish in 2013 and was on the best-seller list for months and won the Readers’ Prize 2014 in Denmark. It came out in the UK on November 6, 2014 and in the US on April 7, 2015.

NOTES:
Non-specific effects of vaccines - difference form placebo - clarification Non-specific effects page vaccines reference to Non-specific effects BCG, Polio, Smallpox etc. non-specific effects

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