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Combination And Multiple Vaccinations: A Mixed Reaction

By: Dr. F. Edward Yazbak

3 and [1 +1] ≠ 5

U.S. pediatricians may or may not have noticed the eye-catching headline in the October issue of Pediatric News: "Immunogenic Surprises Limit Combo Vaccines."

The article by Nancy Walsh started, "Efforts to develop combination vaccines that would streamline immunization schedules have hit some surprising snags including unpredictable immunogenicity, Jim P. Buttery, MD, said at the international congress of the world Society for Pediatric Infectious Diseases."

Buttery, who is research director at the Murdoch Children's Research Institute at the University of Melbourne, had also published his findings in the Journal of the American Medical Association (JAMA) in April 2005 under the title: "Immunogenicity and safety of a combination pneumococcal-meningococcal vaccine in infants: a randomized controlled trial." (1)

According to the JAMA paper, Buttery was in England at the time of the study and with 12 co-investigators was part of the Oxford Vaccine Group, Centre for Clinical Vaccinology and Tropical Medicine at the University of Oxford.

In the United States, research articles about vaccines planned for infants are usually published in American pediatric or infectious disease journals and given a lot of publicity. British research is also more likely to be published in British medical journals and to be picked up promptly by the lay press. Why this particular British research dealing with pediatric vaccines aimed at a U.K. pediatric population was published in JAMA is not clear. In all likelihood, few pediatricians in both countries were aware of its publication and its findings.  

The study by Buttery and associates was aimed at evaluating the safety and immunogenicity of combining two vaccines: A 9-valent pneumococcal vaccine and a group C meningococcal conjugate vaccine - so that they could be administered by a single injection as part of the U.K. routine infant vaccination schedule at age 2, 3, and 4 months.

The study, a phase-2 randomized controlled trial was obviously planned more than five years ago and was conducted from August 2000 to January 2002. Some 240 healthy infants aged 7 to 11 weeks were enrolled.  Home follow-up visits were done at ages 2, 3, 4, and 5 months.

A combination pneumococcal and monovalent group C meningococcal conjugate vaccine was administered to 120 infants. The control group of 120 infants received the monovalent group C meningococcal conjugate vaccine but no pneumococcal vaccine. Simultaneously, all 240 infants (both groups) received their "routine" vaccinations: DTwP (diphtheria, tetanus and whole-cell pertussis), HIB (haemophilus influenzae B) and OPV (oral polio vaccine).

There was reduced group C meningococcal immunogenicity, when the pneumococcal and meningococcal vaccine combination was administered, compared with the meningococcal vaccine alone. More interestingly, the immunogenicity of concomitantly administered HIB and DTP vaccines was also diminished. Immunogenicity of the pneumococcal component of the combination was not affected.

The authors concluded that the fact that the Meningococcal C immunogenicity is reduced, when the vaccine is combined with the 9-valent pneumococcal vaccine, essentially limits further development of the combination.

That obviously makes a lot of sense.

But then a very important question must be asked: If the polyvalent pneumococcal vaccine reduces the protective ability of DTP, HIB and menigococcal C vaccines, then should it ever be administered on the same day at another site?

The logical answer should be no.

* * *

The U.K. Vaccination Schedule

The following vaccination schedule has been recommended in the United Kingdom since 2004: Pediacel® and a meningococcal C vaccine (Meningitec®, NeisVac-C®) injected at different sites at the age of 2, 3 and 4 months. (2) It appears that the British experience with meningococcal C vaccine has been positive. (3) That of other countries has not been.

Pediacel® contains DTaP (diphtheria, tetanus and acellular pertussis), HIB and IPV, the inactivated polio vaccine. Unlike the old DTP, Pediacel® is thimerosal-free.

Not too long ago, the adoption of a new DTaP + HIB combination in the U.K. was promptly followed by an inordinate number of cases of haemophilus influenzae B illness among fully vaccinated children and thousands had to be recalled for another HIB dose. The health authorities claim that this problem will not happen with Pediacel because another strain of HIB vaccine has been incorporated in Pediacel and the National Health Service (NHS) has reassured parents that the problem has been corrected: "Previously Hib vaccine mixed with acellular pertussis vaccine was not as effective as mixed with whole cell. A reduction in the Hib response when given in combination with an acellular pertussis vaccine appears to be brand specific. Studies with Pediacel have shown that the Hib response is similar when given in combination or separately. This is one of the reasons Pediacel was chosen." (4)

The national vaccination program for meningitis C in the U.K. started in the autumn of 1999. It is now evident that a meningococcal-pneumococcal combination vaccine was planned since then - if not earlier - because the Oxford research, a Phase-2 study, actually began in August 2000 and the planning, funding and setting of such research can easily take a year.                                                                                                                                

A similar situation happened in the U.S., when Varivax®, the varicella vaccine was launched. Plans were immediately put into motion to combine it with the MMR®. MMR-V was recently licensed under the name ProQuad®. (5)

* * *

In the United States, the available meningococcal vaccine is polyvalent and is not administered as part of the initial pediatric vaccination schedule. A recent entry into the U.S. market seems to have had problems already. Menactra®, a quadrivalent (A, C, Y & W135) meningococcal conjugate vaccine (MCV4) manufactured by Aventis Pasteur was licensed on Jan. 14, 2005.

The Advisory Committee on Immunization Practices (ACIP) recommended its use at age 11 to 12 or, if missed, at high-school entry. Routine vaccination was also recommended for first-year college students living in dormitories and for "other persons at increased risk." (6) Following five reports in quick succession to VAERS, the FDA and the CDC issued an Alert on Menactra Meningococcal Vaccine and Guillain Barre Syndrome and asked that reports of new cases of GBS be promptly filed with VAERS "to help the agencies further evaluate the matter." (7)

Interestingly, Aventis Pasteur recalled several lots of a similar vaccine (Menomune®-A/C/Y/W-135) in October 2002. (8)

* * *

Prevnar, The U.S. Pediatric Pneumococcal Vaccine

Prevnar® , a pediatric heptavalent pneumococcal vaccine (PCV 7), is the product recommended and used in the United States. It is manufactured by Lederle and is administered with other vaccines at 2, 4, 6 and 15 months of age as a separate injection at a different site. It was licensed in February 2000. Of note is the fact that the British pediatric vaccine is 9-valent and that both pediatric vaccines are totally different from Pneumovax®, the adult 23-valent pneumococcal vaccine manufactured by Merck.

A review of Prevnar by Michael Horwin, MA, published in September 2000 (9) is a classic example of how an investigative report should be done. It is recommended reading for anyone who wants to know "everything" about this vaccine.

Regarding interference of Prevnar with other vaccines, the following quotes from the 2000 package insert are worth noting:

  • "Although some inconsistent differences in response to pertussis antigens were observed, the clinical relevance is unknown."
  • "MMR and varicella immunogenicity data from controlled clinical trials with concurrent administration of Prevnar are not available."
  • "The response to two doses of IPV given concomitantly with Prevnar "¦ (was) lower for (poliovirus) Type 1."

Vaccine interference in the most recent (2005) Prevnar package insert was described somewhat differently. (10)

          Simultaneous Administration with Other Vaccines

During clinical studies, Prevnar ® was administered simultaneously with DTaP and HbOC, IPV, Hep B vaccines, MMR, and varicella vaccine. Thus, the safety experience with Prevnar® reflects the use of this product as part of the routine immunization schedule.

The immune response to routine vaccines, when administered with Prevnar® (at separate sites), was assessed in 3 clinical studies in which there was a control group for comparison. Higher antibody levels (GMC) to Hib were observed after 3 doses of HbOC given with Prevnar in the infant series, compared to HbOC without Prevnar. After the 4th dose, Hib GMCs were lower when HbOC was given with Prevnar compared to control; however, over 97% of children receiving HbOC with Prevnar achieved a serum antibody concentration of >/=1 µg/mL. Although some inconsistent differences in response to pertussis antigens were observed, the clinical relevance is unknown. The response to 2 doses of IPV given concomitantly with Prevnar®, assessed 3 months after the second dose, was equivalent to controls for poliovirus Types 2 and 3, but lower for Type 1. In another study, over 98% of subjects achieved neutralizing antibody titers >/=1:8 for all polio types, following a third dose of IPV given concomitantly with Prevnar at 12 months of age. Seroresponse rates to measles, mumps and rubella were similar after MMR was given concomitantly with Prevnar at 12 months of age compared to seroresponse rates after MMR was given without Prevnar at 12 months of age. Varicella immunogenicity data from controlled clinical trials with concurrent administration of Prevnar® are not available.

Interesting Observations

  • Five years later, the "clinical relevance" of the inconsistent differences in response to pertussis antigens in the U.S. studies was still unknown. The diminished immunogenicity of the DTP in the Oxford University study was a fact.   
  • The U.S. studies showed a dip in HIB antibodies with the fourth dose (15 months) but "higher antibody levels" after the first three doses. That a "synergistic effect" occurred in infancy is unique; that it was followed by a drop in antibody levels after the "booster" at 15 months, when the baby's immune system is more competent is even stranger. The British study was unequivocal: there was reduced immunogenicity of the HIB vaccine following the first three doses.
  • The problem with Polio Type I immunity is serious. Polio I is the strain responsible for most epidemics and the one that causes most paralytic cases.
  • The statement "Seroresponse rates to measles, mumps and rubella were similar after MMR was given concomitantly with Prevnar at 12 months of age compared to seroresponse rates after MMR was given without Prevnar at 12 months of age" does not confirm that the level of immunogenicity was good; it simply states that it did not change.
  • The non-availability of the "Varicella immunogenicity data from controlled clinical trials with concurrent administration of Prevnar®" after five years is also a concern. Were they ever done or were they so negative that they could not be revealed?

Post-Marketing Experience

<< Administration site conditions: dermatitis, urticaria, pruritus.
Blood and lymphatic system disorders: regional lymphadenopathy. Immune system disorders: hypersensitivity reaction including face edema, dyspnea, bronchospasm; anaphylactic/anaphylactoid reaction including shock Skin and subcutaneous tissue disorders:  angioneurotic edema, erythema multiforme

There have been spontaneous reports of apnea in temporal association with the administration of Prevnar. In most cases Prevnar was administered concomitantly with other vaccines including DTP, DTaP, hepatitis B vaccines, IPV, Hib, MMR, and/or varicella vaccine. In addition, in most of the reports existing medical conditions such as history of apnea, infection, prematurity, and/or seizure were present. (10) >>

Unfortunately, it is true that as long as several vaccines are administered together, it is impossible to know for sure which one, or two or three, caused a particular baby to have a life threatening event (ALTE) or die.

VAERS reports of certain events that followed the administration of Prevnar, usually with other vaccines, are listed in Table I.

Reports 9,640
Deaths 286
ER visits 3,831
Hospitalization 1,081
Apnea 224
Arrest 51
Seizures 194
SDH 7
RH 5
SBS 3
SIDS 124
Table I
VAERS Reports for Prevnar
1990 through the end of 2004

[In most cases, other vaccines were also administered.]

Pediarix, The Latest U.S. Combination Vaccine

Pediarix® (GSK) is quickly gaining popularity. It contains DTaP, Hepatitis B vaccine (HBV) and IPV. Babies who receive Pediarix® at 2, 4 and 6 months of age actually receive FOUR doses of HBV because they would have usually already received a single HBV during the nursery stay. The "Standard" 3-dose schedule recommended by the ACIP is 0, 1 and 6 month of age.

The 2004 Pediarix® (GSK) product insert (11) lists the following side-effects of the combination vaccine:

Any vaccine may have some side effects but it is possible that your child will have no side effects from vaccination. Side effects with PEDIARIX included pain, redness, or swelling at the injection site, fever, and fussiness. Fever occurred more often with PEDIARIX than when separately administered vaccines were given. Fever most commonly occurred on the day of vaccination and the day after vaccination and typically resolved within a 4-day period following the shot.
Other side effects that your child may experience include diarrhea, loss of appetite, vomiting, crying more than usual, and sleeping more or less than usual. These effects usually clear up within a few days. If these events continue or become severe, tell your doctor.
As with any vaccine, there is an extremely small risk of allergic reactions. Hives, swelling of the throat, and difficulty in breathing are signs of an allergic reaction. If any of these events occur, you should seek treatment immediately. Such rare reactions usually occur before leaving the doctor's office.
Brain or nervous system disease, collapse or periods of unconsciousness or lack of awareness, and seizures have occurred with other pertussis-containing vaccines. Other serious events including death have occurred after vaccinations; however these risks are extremely small.
If you notice any other problems following vaccination, please inform your doctor.

Typically, the CDC comment about combination vaccines is, "The available scientific data show that simultaneous vaccination with multiple vaccines has no adverse effect on the normal childhood immune system. A number of studies have been conducted to examine the effects of giving various combinations of vaccines simultaneously. These studies have shown that the recommended vaccines are as effective in combination as they are individually, and that such combinations carry no greater risk for adverse side effects." (12)

This report has shown:

  • Combinations are not always as effective as their components
  • They do carry a greater risk of side effects (GSK)
  • Even deaths have occurred rarely after vaccination (GSK)

Obviously, the CDC knows that death occurs following vaccination and that it is compensated under VICP, the National Vaccine Injury Compensation Program: "Awards to the estate in a vaccine-related death are limited to $250,000 plus attorney’s fees and costs." (13)

The CDC's (and other experts') statement that "simultaneous vaccination with multiple vaccines has no adverse effect on the normal childhood immune system" is simply wrong: Many infants without immune deficits have been injured by monovalent and mega-vaccines and their injuries have been acknowledged and compensated by VICP.

On the other hand, if indeed it is true that infants with "normal" immune systems are not affected by simultaneously administered multiple vaccinations, shouldn't health care providers check the infants' immune system thoroughly before giving them a single or a battery of vaccines? This is particularly true in the case of micro-preemies, who weighed less than two pounds at birth and who we are now vaccinating with six and seven antigens at the "chronological age" of 2 months, often before there were due to be born and more often when they are still recovering from major difficulties. Is anyone certain that their immune system is normal? And what risk of disease are they running in the neonatal intensive care unit?   

Not all vaccine injuries are "immune" or autoimmune in nature. Many infants simply stop breathing and go on to a full cardio-respiratory arrest following vaccination. If they are found dead, they are usually presumed to have died of SIDS and not because of the multiple vaccinations they have just received. (For a review, please go to http://www.staticfreesoft.com/vaers/. Under symptoms, type SIDS and search.)

If the anoxia is prolonged, because small babies are hard to ventilate and intubate, brain edema may result and may be followed by subdural and retinal hemorrhages. The vaccine reaction will then be presumed to be Shaken Baby Syndrome and will not be reported to VAERS. In addition, the unlucky adult who happened to be alone with the baby at the time of the ALTE will be accused of the "crime" and considered guilty until proven innocent.

* * *

In September 2005, the European Medicines Agency suspended the use of the Hexavax vaccine because of inadequate immunogenicity of its hepatitis B component. Hexavax is marketed by Aventis Pasteur and Merck and contains diphtheria, tetanus, acellular pertussis, IPV, HIB and HBV. (14)

Conclusions

  • A quiet British study confirmed again that the concomitant administration of several vaccines may affect the effectiveness of some of their components
  • The vaccine authorities believe that all infants can tolerate any number of vaccines
  • They are clearly wrong

 

References

  1. Buttery JP, Riddell A, McVernon J, Chantler T, Lane L, Bowen-Morris J, Diggle L, Morris R, Harnden A, Lockhart S, Pollard AJ, Cartwright K, Moxon ER. Immunogenicity and safety of a combination pneumococcal-meningococcal vaccine in infants: a randomized controlled trial. JAMA. 2005 Apr 13;293(14):1751-8.
  2. http://www.prodigy.nhs.uk/guidance.asp?gt=Immunizations%20-%20childhood
  3. Balmer P, Borrow R, Miller E. Impact of meningococcal C conjugate vaccine in the UK. J Med Microbiol. 2002 Sep;51(9):717-22
  4. http://www.immunisation.org.uk/
  5. ProQuad: The new kid on the block                           http://www.redflagsdaily.com/yazbak/2005_sep26.php
  6. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5440a6.htm
  7. http://www.fda.gov/bbs/topics/NEWS/2005/NEW01238.html
  8. http://www.cdc.gov/nip/vacsafe/concerns/recalls/20021018stmt.rtf
  9. http://www.whale.to/v/prevnar2.html
  10. http://www.drugs.com/pdr/Prevnar_for_Injection.html
  11. http://www.pediarix.com/docs/patient_information.pdf
  12. http://www.cdc.gov/nip/vacsafe/concerns/gen/multiplevac.htm#5
  13. http://www.hrsa.gov/osp/vicp/qanda.htm#10
  14. http://www.businessweek.com/investor/content/sep2005/pi20050921_1739_pi080.htm

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