Are the non-specific effects the same for all vaccines?

The pattern we have observed is that live vaccines have beneficial non-specific effects. This means that after receiving such a vaccine, the person is protected better not only against the vaccine disease but also against (severe) disease with other disease organisms. We can for instance see that the children in Africa who receive these live vaccines have one third lower mortality compared with children, who did not receive the live vaccines. The beneficial effects are strongest in females, so females vaccinated with a live vaccine have lower risk of dying than females vaccinated with a non-live vaccine and lower risk of dying than males vaccinated with the same live vaccine. We have now seen this pattern for four live vaccines (measles-containing vaccine, smallpox vaccine, oral polio vaccine and BCG vaccine against tuberculosis). 

In contrast, we have seen that the non-live vaccines, though protective against the vaccine disease, may increase the risk of other infections, and particularly in the females. This means that African females receiving a non-live vaccine have 1.5-2 times higher risk of dying than females that have not received the vaccine and similar increased risk above that of males vaccinated with the same vaccine. We have now seen that pattern for six non-live vaccines (diphtheria-tetanus-pertussis (DTP)-vaccine, pentavalent vaccine, Hepatitis B vaccine, inactivated polio vaccine, H1N1 influenza vaccine and RTS,S malaria vaccine).  

Learn more:

Layman article about the principles of non-specific effects in Danish and in English

Long scientific review about non-specific effects (Lancet Infect Dis 2020)

Are the non-specific effects the same in males and females?

The pattern we have observed is that the live vaccines have particularly beneficial non-specific effects for females, and the non-live vaccines have particularly harmful non-specific effects for females. In other words, both beneficial and harmful non-specific effects are most pronounced in females. This may be explained by the underlying differences in the immune system of males and females.

Why have the non-specific effects of vaccines not been discovered before?

Everybody was so sure that vaccines would only induce specific protective effects against the vaccine disease organism, that it did not seem necessary to test whether the vaccine affected the risk of other diseases. Therefore, none of our currently used vaccines were tested for such effects before being approved and introduced.

Occasionally some researchers noticed that vaccines had more profound effects on overall mortality than anticipated from the protection against the vaccine disease, for instance Calmette, the inventor of BCG vaccine, noted in the late 1920s, that child mortality among vulnerable in Paris was 25%, but it was only 4% in those who received BCG vaccine, much more than explained from preventing tuberculosis, that did not kill that many children.

However, it was not before our group, working in Guinea-Bissau since the late 1970s, discovered that measles vaccine saved many more lives than those from measles infection, and started a systematic investigation of the overall health effects of vaccines, that it was discovered that all vaccine studied until now have different effects on overall mortality than that anticipated based on their effect against the vaccine disease, i.e. they have non-specific effects in addition to the specific effects.

More recently, it has also been discovered that vaccines have non-specific effects on the innate immune system.

Podcast (in English) with Peter Aaby on the discovery of non-specific epidemiological effects of vaccines

Podcast (in English) with Mihai Netea on the discovery of non-specific immunological effects of vaccines

Are the non-specific effects of vaccines generally accepted?

There is now more and more general acceptance of the beneficial non-specific effects of vaccines, for instance the discovery was made a major milestone on Nature’s list of milestones (milestone 13). Non-specific effects of vaccines are also now mentioned in the world’s most acknowledged textbook for vaccines, “Plotkin’s Vaccines”. In 2020, the world’s first conference on non-specific effects of vaccines was organised with support from Wellcome. In 2021, NIH arranged a three-day workshop dedicated to the non-specific effects of vaccines (though they called them “secondary vaccine effects), where lots of new research in the area was presented.   

However, the non-specific effects are still not taken into account when new vaccines are being tested, the phase 1-4 trials are not requested to collect data on the effect of the new vaccine on the risk of other infections. Furthermore, they are still not taken into account in the world’s vaccination programs. The vaccinations are timed to ensure optimal specific protection, but not optimal non-specific effects. The latter would require programs that we made sure that live vaccines were the most recently received vaccines for the majority of childhood.

Learn more:

Video (in Danish): What have we done to alert the WHO to non-specific effects

What do the opponents against non-specific effects of vaccines say?

For many years, opponents have said that it was biologically implausible that a vaccine could affect the immune system more broadly. However, there are now several immunological mechanisms that can explain non-specific effects, e.g. “innate immune training”, “cross-reactive T-cells”, and “emergency granulopoesis”. Hence, non-specific effects are no longer biologically implausible.

Opponents have also complained that most of the studies of non-specific effects of vaccines were carried out by our group in Guinea-Bissau. This is true, but it should be noticed that 1) it is not easy to study non-specific effects, because it requires good timely data on vaccination status – data that not many countries have available, and 2) it may have scared researchers away that the topic was controversial. Noteworthy, the non-specific effects of vaccines are not limited to Guinea-Bissau: they have been shown e.g. in other parts of Africa, in South East Asia, and also in Denmark and the US.

What are the public health consequences of non-specific effects of vaccines?

There are two major implications of the discovery of non-specific effects of vaccines. First, the testing of new vaccines should include testing of the vaccine’s effect on other infections. Second, vaccination programs should be designed so they optimize not only the specific but also the non-specific effects of vaccines.

Learn more:

Video (in Danish): How should vaccine programs be designed to obtain the greatest effect on overall health

What would be needed to start taking non-specific effects of vaccines into account in the vaccination programs?

In our view, we could already now implement some of the changes that the discovery of non-specific effects indicates:

• BCG at birth should be recommended for all children in low-income settings (also children with low birth weight who in some places are recommended delayed BCG)
• Efforts to provide BCG within the first 7 days of life should be strengthened – currently the median age is more than 1 month – too late for the infants to benefit from the non-specific effects of BCG in the neonatal period.
• We should not give a non-live vaccine after a live vaccine or together with a live vaccine as this will reduce the non-specific benefit of the live vaccine.
• We should consider giving more boosters of live vaccines since we have found such booster to enhance the beneficial non-specific effects.
• Since mother’s vaccination status enhance the benefit of live vaccines provided to the newborn child, we should explore systematically how these effects can be optimised.

In a podcast with the “grandfather” of vaccines, Professor Stanley Plotkin, he points out that he thinks the time is due to start using vaccines for their non-specific effects.

At the Optimmunize conference in November 2022, we will be discussing with policy makers what more needs to be done before we can start using vaccines for their non-specific effects.

What is needed to build confidence in vaccines

To maintain public trust, it is essential to document that a given vaccine is associated with improved overall health (not just reduction in the vaccine disease, as the documentation of non-specific effects of vaccines has made it clear that the effect on the vaccine disease cannot be used as a basis for predicting the effect on overall health. In the long run, confidence is built with good data on vaccine effects on overall health and with honesty.

Video (in Danish): How to ensure public trust in vaccines

Video (in Danish): Thoughts on the vaccine debate