Vaccines – an unresolved story in many ways

In the past 40 years, Danish research has shown that the story of vaccines is not quite as simple as the World Health Organization, national health authorities and others portray it.

For 40 years, Danish researchers from Statens Serum Institut and the University of Southern Denmark have shown that vaccines against everything from polio and smallpox to malaria and tuberculosis have both beneficial and harmful health effects that are unrelated to the diseases the vaccines protect against.

Now these researchers have put the research into a historical perspective that they hope can help to make the world’s health authorities realize that the relationship between vaccines and disease is not always simple.

In fact, their research shows that some vaccines protect against completely different diseases than those for which they are designed. Unfortunately, other vaccines are associated with excess mortality from unrelated diseases.

According to Clinical Professor Christine Stabell Benn from University of Southern the topic is so sensitive that many health authorities, including the World Health Organization (WHO), have so far decided to ignore the truth that some Danish researchers tell them they have known for a long time.

“What do researchers do when they discover that vaccination opponents are justified in being concerned? No vaccines have been studied for their non-specific effects on overall health, and before we have examined these, we cannot actually determine that the vaccines are safe. In addition, our research shows that some vaccines actually increase overall mortality, especially among girls, and this is very worrying,” explains Christine Stabell Benn, Clinical Professor, University of Southern Denmark, Odense.

Christine Stabell Benn and colleagues recently published a summary of their past 40 years of research on the non-specific effects of vaccines in Clinical Microbiology and Infections.

Measles vaccine has other protective effects

Christine Stabell Benn’s research saga began in 1979 when her colleague, Peter Aaby, travelled to Africa to investigate why so many children died there.

A study by the Swedish International Development Cooperation Agency had previously shown that only about half of the children in Guinea-Bissau survived until age 5 years.

At the time, the assumption was that these children died from malnutrition, but Peter Aaby was astonished to discover that only 2 of 1200 children in the suburb of Bandim were severely malnourished. There had to be another reason for the very high child mortality.

A devastating measles epidemic broke out in Guinea-Bissau when Peter Aaby was there. Every fifth infected child died from measles or its associated complications. However, the children who died turned out to be as well nourished as those who survived. Measles also killed healthy children.

Peter Aaby’s team therefore started vaccinating the children in Bandim and founded the Bandim Health Project. Already the following year the team were very surprised to find that the mortality rate among vaccinated children was 70% lower than among those who had not received the vaccine. This was much more than the 10–20% that could be explained by protection against measles alone.

“What Peter found could not be explained by the vaccine’s protection against measles. It was a very mysterious discovery, because it indicated that the measles vaccine protected against infectious diseases other than measles. This was the first time the current paradigm that a vaccine only affects the target disease had been questioned,” says Christine Stabell Benn.

Measles vaccination caused child mortality to decline in other countries

In the early 1980s, Peter Aaby set out to find out whether his discovery in Guinea-Bissau was an isolated case. However, it soon became apparent that the non-specific effect of measles immunization was general. He found the same effect among children in Burundi, Bangladesh and Senegal.

In all countries, mortality among children declined by more than 50% after measles vaccination started. Again, this was a much greater decline than protection from measles alone could explain.

“Peter investigated this for 10 years. His idea was that perhaps the measles infection subsequently contributed to excess mortality, but over time it became clear that the protective effect was decoupled from measles and instead resulted from a non-specific effect in strengthening the immune system to enable the body to protect better against other infectious diseases,” says Christine Stabell Benn.

Specifically, Peter Aaby discovered that mortality from infectious diseases of the lungs, such as bronchitis and pneumonia, declined substantially as a result of measles immunization.

New measles vaccine doubled girls’ mortality from other infectious diseases

The original vaccine, which had the extra beneficial effects, could only be given around 9 months of age, when maternal antibody had waned. However, in 1989, WHO introduced a new measles vaccine in Africa that could immunize children already at 4–5 months of age.

This seemed like good news, because the new vaccine could increase children’s survival by protecting them earlier against measles, and Peter Aaby and colleagues also hoped for even stronger non-specific benefits.

To their surprise, however, they experienced something completely different and very alarming when they tested the new vaccine on the Bandim Health Project’s study population: the new vaccine did protect against measles, but the vaccine doubled overall mortality among girls.

“The vaccine was rolled out in Gambia, Senegal and Guinea-Bissau, and the results were very clear: it caused several girls to die from infectious diseases. So we had a vaccine that protected against measles but increased the risk of dying from other causes. Peter contacted WHO immediately after the discovery, but they did not believe his results. WHO did not withdraw the vaccine until 1992, when other studies showed the same results in Sudan and Haiti,” explains Christine Stabell Benn.

The discovery that a protective vaccine could be associated with higher and sex-differential mortality should have revolutionized vaccine research, but Christine Stabell Benn believes that because the vaccine was only tested in Africa and caused African children to die, it did not attract as much attention as it should have.

“Imagine if this had happened in Europe. There would have been a massive outcry, but the story of the African children was swept under the carpet,” she says.

Diphtheria-tetanus-pertussis (DTP) vaccine increased mortality among children

In 1992, Christine Stabell Benn joined Peter Aaby in Guinea-Bissau. By that time, Peter Aaby had expanded the study area to cover three districts, and Christine added another district. Since then, the study area was expanded to the current six districts and 100,000 individuals in the city and an additional 100,000 individuals in rural areas. Together, the researchers began investigating the effect on overall mortality of many vaccines.

In the ensuing decades, their findings showed that the bacillus Calmette–Guérin (BCG) vaccine for protection against tuberculosis has the same beneficial effect on the immune system as the original measles vaccine.

The findings, which were later confirmed in randomized trials, were initially produced by determining child mortality after the Bandim Health Project team had dispensed vaccines. Children who received the BCG vaccine had considerably lower mortality than children who did not receive the BCG vaccine.

Nevertheless, the researchers found that the DTP vaccine that protected against diphtheria, tetanus and whooping cough did not cause the same decline in mortality. In fact, the DTP vaccine was associated with the same excess mortality as the new measles vaccine.

“The DTP vaccine doubled mortality among children younger than 5 years, and especially for girls. This is extremely high. In addition, DTP is the world’s most widely used vaccine, and there is a huge incentive to use it because it protects against some diseases that you certainly do not want to get,” explains Christine Stabell Benn.

Six of 10 vaccines investigated were associated with increased mortality

Peter Aaby and Christine Stabell Benn studied nine vaccines throughout the 1990s and into the 2000s.

They found that the live vaccines containing the disease-causing organism in a live but attenuated version – the old measles vaccine, the BCG vaccine, oral polio vaccine and the smallpox vaccine – appear to boost the body’s immune response to various infectious diseases that can otherwise result in death.

Among others, the researchers performed a registry study of Danes who had been vaccinated against smallpox before the vaccine was phased out in 1980 and found that those vaccinated appeared to be protected against deadly diseases.

The research results also showed that the smallpox vaccine and the BCG vaccine provide 30% protection against acquiring HIV, similar to specific HIV vaccines.

In contrast, the five non-live vaccines the researchers studied were: DTP vaccine, pentavalent vaccine, inactivated polio vaccine, H1N1 influenza vaccine and hepatitis B vaccine. These all increase the overall mortality rate, especially among girls, even if they protect against the target diseases.

“Our new article focuses on the beneficial effects, since communicating this message is a little easier. However, we have found that various vaccines have either negative or positive effects. We examined the vaccines for common features and found that the live attenuated vaccines have the beneficial non-specific effects, whereas the non-live vaccines produce the adverse effects, especially among girls,” says Christine Stabell Benn.

Malaria vaccine increased mortality among girls

In recent decades, GlaxoSmithKline has been working on a new antimalarial vaccine, and the results of the trials of the new vaccine were published in The Lancet in a blaze of publicity.

The vaccine provided 18–36% protection against malaria, more than any other previous vaccine.

This a potentially important step towards preventing a disease that kills millions of people each year, but Christine Stabell Benn and Peter Aaby scrutinized the research results and found that the vaccine did not reduce mortality.

Overall mortality was 24% higher among people who had been vaccinated against malaria compared with unvaccinated individuals.

“A vaccine that protects against malaria that does not reduce mortality makes no sense. We therefore asked GlaxoSmithKline for access to the original data and found that the vaccine reduced mortality among boys by a modest 15% while doubling the overall mortality rate for girls. This was the sixth non-live vaccine that we associated with increased mortality among girls – exactly as we had seen for other non-live vaccines,” says Christine Stabell Benn.

The researchers published their alarming findings, but WHO is now rolling out the vaccine in Africa.

BCG vaccination protects against yellow fever

The numerous research results during the past 40 years put Christine Stabell Benn, Peter Aaby and their colleagues in a difficult dilemma. What should they do when there is obviously cause for concern about some vaccines while other vaccines being phased out, like smallpox vaccine and soon also oral polio vaccine, appear to have some beneficial non-specific effects?

“We have so many data now that show beyond a doubt that vaccines can affect the immune system in a way that makes the body better or worse equipped to deal with other infectious diseases,” says Christine Stabell Benn.

In support of her argument, she emphasizes the results of an experiment with the BCG vaccine, in which the researchers first gave a group of volunteers in the Netherlands the BCG vaccine and 4 weeks later the yellow fever vaccine, which contains attenuated yellow fever virus. The results showed that those who had been given the BCG vaccine subsequently had less yellow fever virus in their blood.

The BCG vaccine therefore protected against yellow fever virus, although this is a completely different pathogenic organism than tuberculosis, for which BCG vaccine was developed.

Greater focus on the non-specific effects of vaccines

Christine Stabell Benn maintains that the research results do not support scrapping all vaccinations and waiting 30 years for researchers to know more before introducing them again.

Instead, she suggests focusing on the non-specific effects of vaccines when introducing new vaccines or phasing out old ones.

One example of this is introducing the human papillomavirus vaccine for boys in Denmark: at the introduction, there could be a transitional period of 3 years in which half of the boys receive the vaccine and half do not.

This would enable follow-up to determine the effects of the vaccine other than reducing the risk of being infected with human papillomavirus.

“When introducing new vaccines, we have a window of opportunity in which we can learn more about the non-specific effects of the vaccines, and this knowledge can help us to make better decisions. We can determine how much improvement in health we actually get for the money spent. In some cases, hiring more nurses may actually be more beneficial than introducing a new vaccine that protects against a given disease but does not improve overall health,” says Christine Stabell Benn.

All Danes should be included in research throughout their lives

Christine Stabell Benn explains that her overall mission is to involve all Danes in research throughout their lives to help to create health data that the healthcare system can use to make better decisions.

This may be in connection with introducing or phasing out vaccines but also in relation to surgery, hospitalization and other areas in which data collection and variation in treatment can produce important knowledge for improving the healthcare system.

“I think we should become world champions in examining ourselves. We must also do this based on the current reluctance for vaccination, which we must take very seriously. We have to explain to people what we are doing and why, and if we are not entirely sure then we need to tell them. However, we should also not discontinue vaccines until we know whether we are also eliminating some beneficial effects on health that we have not investigated,” says Christine Stabell Benn.

Danes should not be worried

Christine Stabell Benn says that her children have been vaccinated and that she is not that worried because Denmark’s vaccination programme is very conservative.

Nevertheless, she thinks that investigation should determine whether there is room for improvement – especially given the research findings she and Peter Aaby have published.

For now, it seems sensible that the early phase of Denmark’s vaccination programme ends with the live umbrella vaccine as done today.

Conversely, children receive an MFR booster vaccine at 4 years and DTP at 5 years.

The MFR vaccine is live, and the DTP vaccine is non-live.

“Our results suggest that giving these two vaccines in the opposite order could improve overall health. Here too, I think, researchers should investigate what happens if the order is switched. Maybe the general health effect will be much greater, and this is well worth considering,” says Christine Stabell Benn.

Christine Stabell Benn is also pleased that she has not had any children in the United States, where, for example, all newborns have the mandatory non-live hepatitis B vaccination four times before their first birthday.

“I would not voluntarily give my newborn the hepatitis B vaccine let alone want to be forced to do it. Vaccination this early only makes sense if the mother is chronically infected with hepatitis B, for which there is a test, and only a few percent have it. So the vast majority of infants who get the vaccine at birth do not need it, and no one has tested what the vaccine means for overall morbidity and mortality. The only study to investigate this is our study, showing that hepatitis B is associated with higher female than male mortality, which is a serious danger signal given our results for other non-live vaccines,” says Christine Stabell Benn.

“Developing the concept of beneficial non-specific effect of live vaccines with epidemiological studies” has been published in Clinical Microbiology and Infection. In 2014, the Novo Nordisk Foundation awarded a grant to Christine Stabell Benn for the project Smarter Use of Vaccines: Improving Health in Both Man and Livestock Through a Better Understanding of Non-specific Effects of Vaccines.