Vaccine Issues 2013: 
The Non-Specific Effects of Vaccination

Jacob Schor ND, FABNO
September 21, 2013
DNC News

Right about this time of the year we start getting calls about the flu-vaccine, the "should I really get this shot or not?" phone calls. There are a number of vaccine related issues worthy of consideration this year. We will send our several newsletters about vaccines and about preventing and fighting the flu over the next month or so. This first article will cover the non-specific effects of vaccines, a topic that is rarely mentioned and which provides a useful perspective on any discussion of the pros and cons of vaccination policies.

I am going to write about some recent research about vaccines as I think it could change the way we think about vaccination. It helps define some of our concerns about vaccination as well as suggests ways to make better use of certain vaccines.

It is time to expand the definition of vaccines. The old definition suggests that vaccines improve immunity only against a particular disease. 
“A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism and is often made from a weakened or killed form of the microbe, its toxins or one of its surface proteins. The agent stimulates the body’s immune system to recognize the agent as foreign, destroy it and remember it so that the immune system can more readily recognize and destroy any of these organisms that it later encounters.” [1]

A newer and more expansive definition is needed as the evidence tells us that vaccines not only protect against the specific diseases they are intended to but, that they also affect resistance to other infectious diseases. This is called their non-specific effect, and these actions can be strongly beneficial or equally detrimental.

This is nothing new. Shortly after Edward Jenner introduced Vaccinia treatments in 1796, the vaccine was reported to have other “…. positive side-effects such as healing of chronic skin rashes, reduced susceptibility to various infectious diseases, e.g. measles, scarlet fever and whooping cough, and even [had] prophylactic use… against syphilis…”.[2] In 1927, Carl Näslund the physician in charge of introducing tuberculosis [bacilli Calmette-Guerin (BCG)] vaccinations in northern Sweden reported that vaccinated children had an almost three times better chance of reaching their first birthday than unvaccinated children. [3] Tuberculosis rarely affected this age group.

Modern research on non-spcific effects of vaccinations was triggered by a mistake.
In 1994, Peter Aaby reported the results of a randomized trial of new measles vaccine in Senegal. The vaccine was given as earlier than usual at 4-5 months of age rather than 9 months. Vaccinated girls were twice as likely to die as those using the older vaccine. [4] Or at least so it seemed at first.

Aaby was and continues to work on vaccination programs sponsored by the World Health Organization (WHO) in areas with high rates of infectious disease such as Guinea-Bissau and Senegal. His 1994 report led to a systematic investigation of all vaccines. This examination revealed that measles, BCG and the Vaccinia (smallpox) vaccines all seem to have beneficial non-specific effects that are beneficial, reducing death rates from a wide range of infectious disease [5,6,7,8] , while DPT can increase risk of females dying from infections other than the three diseases it protects against. It turns out that Aaby’s 1994 data was misinterpreted. DTP vaccinations had been administered after the measles vaccine, canceling out the beneficial non-specific effects that should have been seen.

Let us review the evidence one vaccine at a time:

Measles Vaccine:

A 2012 Africa study, reported that measles vaccine cut deaths from all other infections combined by a third, mainly by protecting against pneumonia, sepsis and diarrhea. In developing countries, measles-vaccinated children have lower mortality rates from all infectious diseases. [9, 10] In 2005, Veirum reported that measles vaccinated children had a 49% decreased risk of fatality from infectious disease. In pneumonia cases there was a 72% decrease risk of dying in the vaccinated children. [11]

Measles vaccine appears to cancel out the negative impact of DPT. A randomized trial conducted from 2003 to 2009 in Guinea-Bissau, an additional dose of measles vaccine was given at 4.5 months. The children had received three DPT shots prior to starting this study. Compared to children who received measles vaccine at 9 months of age, children who received the vaccine at 4.5 months and 9 months had a 30% decrease in all-cause mortality up to 3 years of age. Less than 5% of this reduction in mortality could be explained by measles prevention. [12] 

Bacillus Calmette-Guérin (BCG)

BCG vaccine also has a beneficial non-specific effect. In two studies on low birth-weight (LBW) neonates, early vaccinations cut infant mortality by nearly half, preventing death from other infectious diseases, not from tuberculosis. [13]

The sequence in which vaccinations are received may make a difference. The non-specific effect of the last vaccine received is the one that lingers. In 2012, Hirve reported that BCG given out of sequence, so that it is the last vaccination instead of DTP, was associated with lower mortality. Two-thirds of a group of 4,138 children born between 1987 and 1989 in 45 adjacent villages in western India received their BCG and DTP vaccines out of sequence, receiving either both vaccinations at the same time or the BCG after the DTP. The mortality rate ratio for those children was 0.15 compared to those who had been vaccinated on schedule. [14]

An April 2013 paper reported BCG revaccination resulted in a stronger IFN-γ response in 345 infants in Guinea-Bissau. BCG also affected the pro-/anti-inflammatory balance, reducing TNF-α and increasing IL-10 responses to LPS, the effect being stronger in children who had already been vaccinated with DTP. [15] 

A June 2013 published study reports that infant BCG vaccination resulted in more effective responses to subsequent vaccinations. The concentration of antibodies triggered by subsequent vaccines was higher in the BCG immunized children (except for hepatitis B).[16] We might argue that BCG should be the first and last vaccine administered in vaccination programs. Of course such an argument would be moot though as BCG is rarely administered in the US. 

One does have to contemplate whether the homeopathic preparations using these bacteria might have a similar effect.


Vaccinia (Smallpox)
This vaccine has already been phased out in much of the world so the recent studies compare older vaccinated cohorts versus younger unvaccinated groups. In low income countries having a Vaccinia scar is associated with a 40% reduction in overall mortality among adults. Having been vaccinated with small pox is associated with a significantly reduced risk of malignant melanoma and infectious disease hospitalizations. 

Risk of hospitalization in Danish adults decreased nearly 20% if vaccinated before 3.5 years. Risk increased the longer vaccination was delayed. [17] Vaccination with both BCG and smallpox vaccines was associated with a 36% reduction in melanoma risk. [18] 

While on the topic of melanoma, it should also be mentioned that the Yellow Fever vaccine is also associated with lower risk for melanoma; ten years after receiving the vaccine, the odds ratio of getting melanoma for the vaccinated was 0.26 compared to the unvaccinated. [19] 


Diphtheria tetanus and pertussis (DTP)

We have good reason to be concerned about DPT. While measles, BCG and smallpox vaccines have beneficial non-specific effects, DTP vaccine appears to have a negative effect, particularly in females. Girls have higher mortality than males who receive DTP. Negative effects are seen if DTP is the most recent vaccination. Giving BCG or measles vaccine after DTP appears to neutralize the negative effects of DTP. Thus vaccine sequence is important and understanding this has helped unravel some of the confusing data published over the years.

Why?
One problem with this entire non-specific vaccine effects business is that it makes little sense. There has been no clear mechanism of action to explain what is seen and when observations counter current theory, the data becomes easy to ignore. 

For example, a WHO-commissioned review concluded that the benefit of measles vaccine was simply because the vaccine decreased incidence of measles. [20] While two studies support this conclusion, ten others reached the opposite conclusion. [21] 

This concept may not be as implausible as it seems. As naturopathic physicians, it is easy to conceive that every exposure that an individual’s immune system has to infections or vaccinations leaves an imprint that affects future responses of both the innate and adaptive responses to new pathogens. This concept is referred to as heterologous immunity, which explains that non-specific effects may result from vaccines encoding antigens that cross-react with other pathogens. T cell responses could be informed by prior infections with unrelated viruses. 

Vaccination may leave the innate immune response in a heightened state of alertness. This may be an example of ‘trained innate immunity’ in which either a primary infection or vaccination confers protection against a secondary infections. The increase in non-specific resistance of the host to re-infection involves innate immune cells such as macrophages and natural killer (NK) cells and results in improved pathogen recognition and enhanced responses. It’s been put forth that the molecular mechanisms that induce trained immunity involve epigenetic reprogramming.

Perhaps we should leave discussion of these mechanisms until such time when the debate among the scientists on the details has slowed.

There is a paradigm shift taking place in understanding how vaccines act; the new view is that vaccines have non-specific effects on health and survival that are greater than merely protecting against particular diseases. 

There seems to be a trend, that live vaccines like BCG, measles and Vaccinia, are associated with beneficial nonspecific effects that reduce all-cause mortality. In contrast, the inactivated vaccines, DTP in particular, increase risk of other unrelated infections and more so in females. 

This should give us cause for concern. If receiving a live vaccine afterwards offsets the negative impact of DTP, what happens if this rarely if ever occurs? BCG, in particular, while once widely used in Europe, has never been routine in the United States. Even in Europe, BCG is no longer mandatory. While we may talk about BCG lowering infectious disease rates in undeveloped West African countries, we hardly ever use it in the U.S. and so know little about how it affects our population.

Because Europe has stopped using BCG, might we expect an eventual spike in melanoma cases? Krone reported in 2003 and 2005 that the odds ratio of being diagnosed with melanoma dropped by more than half for people who had received BCG or Vaccinia compared to those who had not received these vaccines. [22, 23] If ‘vaccine deficiency’ more than doubles risk of melanoma, we might want to reconsider some of our practices. 

The WHO research reported benefit from the measles vaccine but does tell us if the MMR combination will do the same. Current CDC guidelines suggest giving a child their final DTP vaccination at about the same time or after their final MMR vaccination. Might it be wiser to finish with the MMR vaccine instead of DTP? Or should we bring back a measles only vaccine? For patients who are unwell after DTP vaccination, perhaps a dose of measles or MMR would cancel out that suppression? Even a dose of BCG vaccine might restore healthy immune function? 

Given the significant effects BCG, Vaccinia and Yellow Fever vaccine have on lowering risk of melanoma, should we encourage high melanoma risk patients to get vaccinated? What of patients with existing melanoma? Would these vaccines help them?

What about flu-vaccine? At least one paper suggests it has a non-beneficial non-specific effect. Cowling reported in June 2012 that children given flu vaccine were more than four times as likely to suffer from non-flu viral infections than children given placebo. [24] That’s bad news.

Our esteemed colleague, Thomas Kruzel, has, for many years, vaccinated his cancer patients against typhus. Not that he’s worried they will catch typhus living in Phoenix, but because he believes the vaccines enhances their ability to fight cancer. He administers an initial dose, followed by a second dose 90 days later and then gives yearly boosters. Dr. Kruzel justifies his protocol on Denk and Karrer’s 1970 report that tracked 5,400 Austrians who suffered from typhus between 1945 and 1947. In 1967, 2800 were still alive. Mortality rate due to cancer was significantly lower than the predicted rates. The authors supposed, “the possibility of an immuno-prophylaxis of carcinoma by unspecific stimulation of the defensive mechanism … ” [25] These patients had suffered from the disease, they were not vaccinated.

Vaccines have another advantage, they may stimulate broad immunity without triggering chronic disease the way having the disease might.

While it is more natural to trigger these non-specific immune reactions by exposure to actual diseases, these days few infants will be exposed. Vaccines might be seen as substitute exposure. Actually getting the vaccines may be preferable to the disease. We should be relieved to miss out on such opportunities. Actually experiencing these diseases may have lasting unwanted consequence. Having tuberculosis, pertussis or measles increases the risk of developing, bronchial hyper-responsiveness, asthma, eczema and other allergic diseases. The vaccines do not increase risk of these symptoms but actually lower risk. [26, 27,28] A 2012 meta-analysis reported that having had tuberculosis was linked to greater risk of asthma and eczema, but past immunization with BCG did not raise risk. [29] 

Our profession has a long history of being suspicious of vaccinations. No doubt this is due to our professional forebears seeing adverse reactions, knowledge of which was passed to us through generations of practitioners. It may also be due to our habit of careful observation; our caution with DPT vaccine appears to be justified, especially in girls. We should not rush to judge all vaccines as universally dangerous. This new research certainly suggests that some vaccines are of use.

This concept of heterologus immunity, the idea that one substance might train the immune system to fight a variety of different infectious agents sounds congruent with our naturopathic worldview. Could this explain how the polysaccharides found in medicinal mushrooms and other botanical extracts act to enhance overall immunity? Could we use this concept to predict other useful interactions?

Heresy it may be, but here is my new bottom line:
Exposure to various disease entities may be required for the human immune system to be activated. Vaccines may provide a safer substitute than exposure and actual infection with the disease. Using vaccines against diseases that no longer threaten, may still have value for their non-specific effect stimulating general immunity. Some vaccines have harmful non-specific effects; we need to discriminate between them.

References:

1. http://en.wikipedia.org/wiki/Vaccine

2. Mayr A. Taking advantage of the positive side-effects of smallpox vaccination. J Vet Med B Infect Dis Vet Public Health. 2004 Jun;51(5):199-201.

3. Aaby P, Benn C. Saving lives by training innate immunity with bacilli Calmette-Guérin vaccine. PNAS, 2012, Oct 10. 
Free text: http://www.pnas.org/content/early/2012/10/10/1215761109.full.pdf

4. Aaby P. Sex-specific differences in mortality after high titre measles immunization in rural Senegal. Bull. World Health Organ. 72, 76-770. 
bulletin_1994_72(5)_761-770.pdf 

5. Aaby P, Martins CL, Garly ML, Balé C, Andersen A, Rodrigues A, Ravn H, Lisse IM, Benn CS, Whittle HC. Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial. BMJ. 2010 Nov 30;341:c6495. 
Free PMC Article http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2994348/

6. Aaby P, Martins CL, Garly ML, Rodrigues A, Benn CS, Whittle H. The optimal age of measles immunisation in low-income countries: a secondary analysis of the assumptions underlying the current policy. BMJ Open. 2012 Jul 19;2(4). 
Free text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401826/

7. Aaby P, Roth A, Ravn H, Napirna BM, Rodrigues A, Lisse IM, Stensballe L, Diness BR, Lausch KR, Lund N, Biering-Sørensen S, Whittle H, Benn CS. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J Infect Dis. 2011 Jul 15;204(2):245-52. 
Free Article: http://jid.oxfordjournals.org/content/204/2/245.long

8. Biering-Sørensen S, Aaby P, Napirna BM, Roth A, Ravn H, Rodrigues A, Whittle H, Benn CS. Small randomized trial among low-birth-weight children receiving bacillus Calmette-Guérin vaccination at first health center contact. Pediatr Infect Dis J. 2012 Mar;31(3):306-8.

9. Aaby MP, Samb B, Simondon F, Seck AM, Knudsen KM, Whittle H. [A non-specific, beneficial effect of measles vaccination. Analysis of mortality studies from developing countries]. Ugeskr Laeger. 1996 Oct 14;158(42):5944-8. Danish.

10. Aaby P, Bhuiya A, Nahar L, Knudsen K, de Francisco A, Strong M. The survival benefit of measles immunization may not be explained entirely by the prevention of measles disease: a community study from rural Bangladesh. Int J Epidemiol. 2003 Feb;32(1):106-16.
Free full text: http://ije.oxfordjournals.org/content/32/1/106.long

11. Veirum JE, Sodemann M, Biai S, Jakobsen M, Garly ML, Hedegaard K, Jensen H, Aaby P. Routine vaccinations associated with divergent effects on female and male mortality at the paediatric ward in Bissau, Guinea-Bissau. Vaccine. 2005 Jan 19;23(9):1197-204.

12. Aaby P, Martins CL, Garly ML, Balé C, Andersen A, Rodrigues A, Ravn H, Lisse IM, Benn CS, Whittle HC. Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial. BMJ. 2010 Nov 30;341:c6495. 
Free text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2994348/

13. Benn CS. Small randomized trial among low-birth-weight children receiving bacillus Calmette-Guérin vaccination at first health center contact. Pediatr Infect Dis J. 2012 Mar;31(3):306-8. 

14. Hirve S, Bavdekar A, Juvekar S, Benn CS, Nielsen J, Aaby P. Non-specific and sex-differential effects of vaccinations on child survival in rural western India. Vaccine. 2012 Nov 26;30(50):7300-8. 

15. Andersen A, Roth A, Jensen KJ, Erikstrup C, Lisse IM, Whittle H, Sartono E, Yazdanbakhsh M, Aaby P, Benn CS. The immunological effect of revaccination with Bacille Calmette-Guérin vaccine at 19 months of age. Vaccine. 2013 Apr 19;31(17):2137-44. 

16. Ritz N, Mui M, Balloch A, Curtis N. Non-specific effect of Bacille Calmette-Guérin vaccine on the immune response to routine immunisations. Vaccine. 2013 Jun 26;31(30):3098-103. 

17. Smallpox vaccination and all-cause infectious disease hospitalization: a Danish register-based cohort study. Int J Epidemiol. 2011 Aug;40(4):955-63. 
Free full text: http://ije.oxfordjournals.org/content/40/4/955.long

18. Pfahlberg A, Kölmel KF, Grange JM, Mastrangelo G, Krone B, Botev IN, Niin M, Seebacher C, Lambert D, Shafir R, Schneider D, Kokoschka EM, Kleeberg UR, Uter W, Gefeller O. Inverse association between melanoma and previous vaccinations against tuberculosis and smallpox: results of the FEBIM study. J Invest Dermatol. 2002 Sep;119(3):570-5.
Free full text: http://www.nature.com/jid/journal/v119/n3/full/5601594a.html

19. Mastrangelo G, Krone B, Fadda E, Buja A, Grange JM, Rausa G, de Vries E, Koelmel KF. Does yellow fever 17D vaccine protect against melanoma? Vaccine. 2009 Jan 22;27(4):588-91. 

20. Cooper WO, Boyce TG, Wright PF, Griffin MR. o childhood vaccines have non-specific effects on mortality? Bull World Health Organ. 2003;81(11):821-6. 
Free full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2572354/

21. Aaby P, Jensen H. Do measles vaccines have non-specific effects on mortality?
Bull World Health Organ. 2005 Mar;83(3):238. Epub 2005 Mar 16.
Free PMC Article http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2624208/

22. Krone B, Kölmel KF, Grange JM, Mastrangelo G, Henz BM, Botev IN, Niin M, Seebacher C, Lambert D, Shafir R, Kokoschka EM, Kleeberg UR, Gefeller O, Pfahlberg A. Impact of vaccinations and infectious diseases on the risk of melanoma--evaluation of an EORTC case-control study. Eur J Cancer. 2003 Nov;39(16):2372-8.

23. Krone B, Kölmel KF, Henz BM, Grange JM. Protection against melanoma by vaccination with Bacille Calmette-Guerin (BCG) and/or Vaccinia: an epidemiology-based hypothesis on the nature of a melanoma risk factor and its immunological control. Eur J Cancer. 2005 Jan;41(1):104-17.

24. Cowling BJ, Fang VJ, Nishiura H, Chan KH, Ng S, Ip DK, Chiu SS, Leung GM, Peiris JS. Increased risk of noninfluenza respiratory virus infections associated with receipt of inactivatedinfluenza vaccine. Clin Infect Dis. 2012 Jun;54(12):1778-83.
Free PMC Article

25. Denk W, Karrer K. [Studies on the possibility of immunoprophylaxis of carcinoma]
[Article in German] Osterr Z Erforsch Bekampf Krebskr. 1970;25(1):30-9.

26. Nagel G, Weinmayr G, Flohr C, Kleiner A, Strachan DP; ISAAC Phase Two Study Group. Association of pertussis and measles infections and immunizations with asthma and allergic sensitization in ISAAC Phase Two. Pediatr Allergy Immunol. 2012 Dec;23(8):737-46. doi: 10.1111/pai.12007. Epub 2012 Sep 24.

27. Shim JY, Kim HB, Lee SY, Yu J, Kim WK, Kang D, Lee CG, Ha M, Kwon HJ, Hong YC, Park KS, Lee HR,Hong SJ. Effects of early measles on later rhinitis and bronchial hyperresponsiveness. Ann Allergy Asthma Immunol. 2010 Jul;105(1):43-9. 

28. Steenhuis TJ, van Aalderen WM, Bloksma N, Nijkamp FP, van der Laag J, van Loveren H, Rijkers GT, Kuis W, Hoekstra MO. Bacille-Calmette-Guerin vaccination and the development of allergic disease in children: a randomized, prospective, single-blind study. Clin Exp Allergy. 2008 Jan;38(1):79-85. Epub 2007 Oct 23.

29. Flohr C, Nagel G, Weinmayr G, Kleiner A, Williams HC, Aït-Khaled N, Strachan DP; ISAAC Phase Two Study Group. Tuberculosis, bacillus Calmette-Guérin vaccination, and allergic disease: findings from the International Study of Asthma and Allergies in Childhood Phase Two. Pediatr Allergy Immunol. 2012 Jun;23(4):324-31.