By: Dr. F. Edward Yazbak
What is ProQuad?
- A glorious four-wheeling experience in Southern France?
- A fast roller skate?
- A titanium fishing lure?
- A new vaccine?
- All of the above?
If you answered number 5, you are correct.
In the hills of southern France, sightseers use four-wheel, all-terrain vehicles to enjoy the breathtaking scenery of the "Cotes du Luberon" during the day and relax with the wonderful meals and wines of the region in the evening. "This is the real Provence, full of character. A sweet dolce vita of a climate and pure clean air which just breathes the incredible contrasts between a rich, and variable natural environment: the blue strides of lavender, the subtle nuances of green in the forests, the flamboyant and blinding colors of the cliffs of ochre, or the austere white of the limestone hills." (1, 2)
Roller skates called 429 Pro Quad are supposed to be fast and provide firm ankle support, "soft-touch" comfort lining and a deluxe padded collar. (3)
In a bait shop, the Titanium Pro Quad Spinnerbait lure is recognized by its four hammered 24-carat gold or nickel plated blades - available in two shapes - which simulate baitfish and precede the well-known multicolored lure.(4)
Only experienced and well-informed adults, taking every possible precaution, use these toys.
The French ATV riders (in the photos) are protected from head to toe by high-impact helmets, safety goggles, heavy clothing, gloves and boots. Any reasonable roller skater would never consider lacing up without a first-class helmet and reliable elbow, knee and shin pads. And it is no secret that fishing lures are handled with extreme caution by anglers, who always have their "fisherman tool" handy, just in case of a "lure in the finger" emergency. (5)
Unlike the new vaccine, the ProQuad ATVs, roller skates and lures are used only by mature and consenting individuals, who are fully informed about their dangers and "adverse events."
Parents dealing with vaccination decisions, on the other hand, seem to be going on faith alone, when they allow their one-year-old children to receive multiple vaccines together in an attempt to protect them against diseases that have disappeared or are so rare that medical students start and finish their training without ever seeing a case.
On Sept. 6, 2005, the Food and Drug Administration (FDA) approved ProQuad by Merck. It is a combined attenuated live virus vaccine containing measles, mumps, rubella and varicella viruses for use in children aged 12 months to 12 years. The vaccine was also approved for use "if a second dose of measles, mumps and rubella vaccine is to be administered."
ProQuad, which is, in fact, a combination of MMR II (measles, mumps and rubella) and Varivax (varicella) vaccines, was reported to be similar to its components in immunogenicity, antibody persistence, safety and adverse events. (6)
By an incredible coincidence, when I first saw the ProQuad information, there was a fact box beside it on FAMVIR®, or famciclovir, an antiviral drug used to treat acute herpes zoster (shingles). (6)
It is now well known that a nationwide increase in the incidence of shingles has occurred since the introduction of the chicken pox vaccine in 1995 and that a new vaccine, Zostavax, also by Merck, is being tested to control the recent iatrogenic outbreak of shingles. (7-11)
Although there may be justification for the administration of the measles vaccine in the second year of life, the need for mumps, rubella and chicken pox vaccinations at that age is less obvious.
Mumps is a benign illness in childhood and administration of the mumps vaccine shortly before puberty to those boys who did not have disease-acquired immunity is much more reasonable.
At present, there is no rubella in the United States and the administration of the rubella vaccine to boys and girls at the age of one in order to protect susceptible adults seems at least questionable if not strange. (12) Vaccinating girls shortly before puberty is more logical and would provide superior and longer-lasting immunity.
The administration of the chicken pox vaccine to all U.S. children does not have valid clinical reasons. Its alleged economical benefits - often cited as the real reason for the national recommendation - have now, as demonstrated by G. S. Goldman, PhD, been eclipsed by the larger cost of controlling the resulting shingles outbreak.
After my recent column, "Trust me. I have the statistics to prove it" (7), a Red Flags reader reminded me that the CDC (Centers for Disease Control and Prevention) has actually stated that shingles occur more frequently in individuals who developed chickenpox before the age of 18 months. (13)
It is only reasonable to suspect that the live attenuated vaccine would mimic the natural illness and likewise lead to an increase in the incidence of shingles as demonstrated in several studies, including one sponsored by the CDC.
The CDC's decision to recommend the administration of the chicken pox vaccine at the age of one appears therefore problematic and merits attention.
Whether the Institute of Medicine (IOM) immunization safety review committee is the right body to investigate the recommendation is another story. (14)
It is widely expected that the CDC will deny any guilt and will simply state that it followed the recommendation of the Advisory Committee on Immunization Practices (ACIP), a group of 15 experts selected by the Secretary of Health and Human Services "to provide advice and guidance to the Secretary, the Assistant Secretary for Health, and the Centers for Disease Control and Prevention (CDC) on the most effective means to prevent vaccine-preventable diseases." (15)
Such an excuse is not valid because the two organizations have historically been very close. ACIP's official information is available on the CDC's National Immunization Program Web site; its email address is ACIP@CDC.GOV; and its mailing address is Centers for Disease Control and Prevention, National Immunization Program, Division of Epidemiology and Surveillance, Mail Stop E61, 1600 Clifton Road, NE Atlanta, Georgia 30333
The CDC will undoubtedly also claim that nothing can be done now that the chickenpox vaccine has been incorporated in ProQuad- again supposedly "on the ACIP recommendation" - and because we must protect children from measles "a disease that kills thousands in Africa."
* * *
What's in a name?
When first licensed, the chickenpox vaccine was to be administered at least a month after the MMR vaccine. Later, pediatricians were told that administering the two vaccines in different sites on the same day was acceptable. However, if the chickenpox vaccine was not given with the MMR, it had to be delayed at least a month.
For years, pediatricians have known that there were plans to combine the MMR and Varivax vaccines and that clinical testing was ongoing. Consistently, the new combination vaccine was referred to verbally as MMRV and in written documents as MMRV or MMR-V.
The registered names of the previous monovalent "single" Merck live virus vaccines were Attenuevax (measles), Mumpsvax (mumps), Rubeovax I and II (rubella) and Varivax (chickenpox).
Registered names of the previous combined Merck live virus vaccines were simply the initials of their components: MM (measles"“mumps), MR (measles-rubella) and MMR I and II (measles, mumps and rubella I and II) vaccines.
There were obviously many meetings and reviews concerning MMR-V and it seemed clear that its endorsement by the ACIP and its licensure by the FDA were assured.
A launch in the fall of 2005 was actually anticipated but what was not expected was a sudden change of the vaccine's name from MMR-V to ProQuad sometime during the summer. (16)
The word "makeover" has recently become quite popular in the United States. On TV, we see individuals and homes transformed in front of our eyes in less than an hour. But a vaccine makeover was certainly a new experience for many. Not being fortunate enough to be included in the "inner circle," I have no idea why the name of the new vaccine was suddenly changed to a strange and non-traditional name shortly before licensure.
- Could it be because of the initials MMR and the on-going crisis about MMR vaccination and autism?
- Could it be because any vaccine containing those three initials would not be readily acceptable, particularly in the U.K., where substantial national malaise still persists?
- Was it simply because we will never have a drug called BIOXX or TIOXX?
- Was it just a financial strategy?
- Could it simply have been that someone at Merck was afraid that people would get confused and think that this is a new and improved fifth MMR just like MMR II was the second one out?
The fact is that there never was a hyphen in MMR II and Merck never produced an MMR III or IV; any confusion would, therefore, have been unlikely. Besides everyone involved knew that MMRV and/or MMR-V simply and clearly indicated that there were four components in that vaccine: measles, mumps, rubella and varicella.
Of note is the fact that the suffix "vax" was evident in all remaining Merck vaccines intended for U.S. infants: Comvax, Pedvax-HIB and Recombivax HB.
For reasons unknown, we now have ProQuad standing all alone, incognito.
* * *
Financial circles took quick note of the FDA approval of the new vaccine.
On Sept. 6, 2005, MSN Money announced the news in a long and detailed report. (17)
The report included a relatively short note describing Merck as "a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck discovers, develops, manufactures and markets vaccines and medicines in more than 20 therapeutic categories. The company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service."
This was followed by the usual "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995: "These statements involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck’s business, particularly those mentioned in the cautionary statements in Item 1 of Merck’s Form 10-K for the year ended Dec. 31, 2003, and in its periodic reports on Form 10-Q and Form 8-K (if any) which the company incorporates by reference."
The MSN report also included the following scientific statements about ProQuad:
- "Moreover, according to the report "Combination Vaccines for Childhood Immunization," issued by the ACIP in 1999, "the use of licensed combination vaccines is preferred over separate injection of their equivalent component vaccines"¦. Potential advantages of combination vaccines include reducing multiple injections, improving timely vaccination coverage, reducing the costs of stocking and administration of separate vaccines for health care providers and reducing health care costs for extra health visits, according to the report."
- "Formal studies to evaluate the clinical efficacy of PROQUAD have not been performed. Efficacy of the measles, mumps, rubella and chickenpox components of PROQUAD was previously established in a series of clinical studies with the monovalent vaccines. A high degree of protection from infection was demonstrated in these studies."
- "PROQUAD had a safety profile similar to its components. In clinical trials, the safety of PROQUAD was compared with the safety of M-M-R II and VARIVAX given concomitantly at separate injection sites. PROQUAD was administered to 4,497 children 12 to 23 months of age without concomitant administration with other vaccines. Children in these studies were monitored for up to 42 days post-vaccination."
- "The persistence of antibody at one year after vaccination was evaluated in 2,107 children enrolled in clinical trials. Antibody persistence rates one year after a single dose of PROQUAD were 98.9 percent against measles; 96.7 percent against mumps; 99.6 percent against rubella and 97.5 percent against chickenpox. These persistence rates are similar to those observed at one year with the individual component vaccines, M-M-R II and VARIVAX. The duration of protection from measles, mumps, rubella and chickenpox (varicella) infections after vaccination with PROQUAD is unknown".
- "Vaccination with PROQUAD may not offer 100 percent protection from measles, mumps, rubella and chickenpox (varicella) infection."
- "Caution should be exercised in administering PROQUAD to persons with a history of cerebral injury, individual or family history of convulsions, or any other condition in which stress due to fever should be avoided. The vaccination history of a prospective vaccine recipient should be obtained to determine whether the individual had any previous reactions to any vaccine including PROQUAD, VARIVAX or any measles, mumps or rubella." containing vaccines.
- "PROQUAD is available for ordering. The catalog price of ProQuad is $114.61 per dose purchased as a pack of 10 single-dose vials of lyophilized vaccine with sterile diluent water or $120.25 if purchased as an individual single-dose vial of lyophilized vaccine with sterile diluent water."
* * *
It appears, therefore, that the following facts about ProQuad are acknowledged by its manufacturer:
- Efficacy studies were not done
- Safety studies never exceeded six weeks
- Protection against the four diseases is not 100 percent
- The duration of protection is unknown
- Risks exist
- Cost considerations are the primary advantages of combined vaccines
Of note is the statement that the only efficacy studies listed were those of the monovalent measles, mumps, rubella and chickenpox vaccines and not those of the actual components of the new vaccine namely MMR and Varivax, which would have been more appropriate. This also appears to raise questions about whether such studies were ever done before the existing combinations namely MM, MR and MMR were licensed.
ProQuad does not make much financial sense either. The CDC currently buys MMR II for $16.67/dose and Varivax for $52.50/dose. The total cost of $69.17 is about 60 percent of the cost of a proposed dose of ProQuad.(18)
* * *
In Europe, GlaxoSmithKline/Belgium has also been testing a European version of MMRV, a combination of PriorixÃ” and VarilrixÃ” (GSK). Apparently "attempts to develop such a vaccine were made nearly 20 years ago but were not successful."
So far the new vaccine is still referred to as MMRV. (19)
Forging ahead and starting in April 2005 - before even filing for a license for ProQuad - Merck has embarked on yet another new study "to demonstrate that ProQuad may be administered concomitantly with a fourth dose of Prevnar and a third dose of IPOL without impairing the safety or immunogenicity of vaccines for measles, mumps, rubella, varicella, 7 serotypes of S. pneumoniae or 3 serotypes of poliovirus." (20)
If interested in enrolling your baby in that study, the toll free number is 1-888-577-8839
And so it goes"¦
- Goldman GS. Varicella susceptibility and incidence of herpes zoster among children and adolescents in a community under active surveillance.
Vaccine. 2003 Oct 1;21(27-30):4238-42
- Goldman GS. Incidence of herpes zoster among children and adolescents in a community with moderate varicella vaccination coverage.
Vaccine. 2003 Oct 1;21(27-30):4243-9
- Goldman GS. Using capture-recapture methods to assess varicella incidence in a community under active surveillance.
Vaccine. 2003 Oct 1;21(27-30):4250-5.
- Goldman GS. Cost-benefit analysis of universal varicella vaccination in the U.S. taking into account the closely related herpes-zoster epidemiology.
Vaccine. 2005 May 9;23(25):3349-55
- http://www.cdc.gov/nip/publications/pink/def_pink_text.htm [Chapter 13]
RECURRENT DISEASE (HERPES ZOSTER) Herpes zoster, or shingles, occurs when latent VZV reactivates and causes recurrent disease.
The immunologic mechanism that controls latency of VZV is not well understood. However, factors associated with recurrent disease include aging, immunosuppression, intrauterine exposure to VZV, and varicella at a young age (<18 months)