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The Chickenpox Vaccine by F. Edward Yazbak, MD, FAAP


Of all pediatric mandated vaccination programs, two seem to make even less sense than others. The first is the universal hepatitis B vaccination program, starting shortly after birth and intended to decrease the risk and incidence of primary liver cancer.  The second is the universal pediatric chickenpox vaccination program, the subject of this report.
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My good friend Julienne has been suffering for over 3 months with shingles, a viral illness related to an old chickenpox infection and post-herpetic neuralgia, its most dreaded complication. The term “suffering” hardly describes the excruciating pain she has been experiencing. At times, she has even needed narcotic analgesics to bring down the torture to the “Awful” level on the Richter scale of pain. To make things worse, her left-handed eighty-year-old husband fell and broke his left shoulder. In just three weeks, this very happy and active couple was seriously sidelined and suffering … together.

When Julienne asked me when or where she could have “caught” shingles, I told her as gently as possible that it was probably a gift from her 14-month-old granddaughter who had recently received her MMR and chickenpox vaccines and who comes to visit on Sundays. Her first reaction was a long sad look as if I had stabbed her, a look every grandparent would have easily recognized. Words were not needed, her face said it all: “What nonsense is that and how dare you blame my baby?” After she counted to ten, she asked defensively: “But shingles happen to old people, anyway… right?” I agreed. This was definitely not the time to explain to her the recent United States shingles epidemic.

As the visit went on, I could see the wheels turning as she was thinking about what I had said, still bewildered. She knew I loved to tease but she also knew that I would have never dared under the circumstances. I dropped the subject, she was hurting enough …

When I saw my friends a couple of weeks later, they were still suffering, maybe a little less but still considerably, at times.

Until the mid-nineties, everyone thought that chickenpox was a mild childhood illness that was catchy and made children itch for a few days. It rated somewhere between an inconvenience and a mild nuisance but it was a good excuse for mothers to stay home from work and “bond” for a while. The best part of the day for the poor itchy toddler was bath time when a tubful of tepid Aveeno seemed like heaven and where he could splash and giggle and sing “If you’re happy, and you know it, clap your hands.”

For the longest time, mothers were delighted when their children developed chicken pox because they knew that the disease was so much more severe among adults. In fact, in spite of their doctors’ admonition, mothers sometimes chose to expose their toddlers to chickenpox in order “to be done with it.”

Pediatricians knew that the infection was caused by the varicella zoster virus (VZV) and that children very rarely developed serious omplications, unless they were immune-compromised.

It was also well-known that the elderly developed shingles, a late complication caused by a reactivation of the chickenpox virus. It was postulated that particles of VZV migrated from the chickenpox blisters and moved to the nervous system where they laid dormant for years because of the repeated exposure to chickenpox in the community that boosted the individual’s immunity. If an individual was compromised for any reason, such as by lack of immune competence or stress, the VZV reactivated, moved back through the nerve fibers and invaded the sensory cell bodies in the neighboring skin, eventually causing the typical rash of shingles. Because that last event took a little while, skin sensitivity and pain often preceded the skin eruptions.

Some fifteen years ago, suddenly and out of the blue, chickenpox became a very serious disease and there were multiple TV and press reports about children dying from chickenpox all over the country. Economists weighed in and ominous warnings filled the air: Chickenpox was not only killing kids and adults, it was a national economic disaster that was eventually ultimately going to collapse the United States economy because it kept mothers at home caring for their children instead of at work.

Merck and the CDC joint efforts had succeeded in creating “a need”, a vaccine for chickenpox was developed and the FDA quickly licensed it. After all, our children’s lives and our national economy depended on it.

VARIVAX® was launched to the cheers of the Merck stockholders in 1995 [i] Within less than a year spent figuring out reimbursement, it caught on in a grand way. With time, it became apparent that two doses were required to protect susceptible children and adults and … in 2006, a second dose of VARIVAX® was recommended. The children were not too happy; the stockholders were jubilant and it is rumored that at Merck, people were heard humming: “Double the shots! Double the Fun.” The vaccine is still selling well at $83.77 per dose.

Pediatricians were first told that the vaccine, because it was another attenuated live virus vaccine, had to be administered one month after the MMR vaccine, between 12 and 15 months of age.

This was soon changed!

It was acceptable to give VARIVAX® and MMR on the same day at different sites but … if we did not give them on the same day, then we had to wait a month. This was certainly peculiar but then preventing chickenpox, most often a mild illness in children, did not make much sense either!

Evidently forgetting the uproar about the MMR vaccine, some bright people at Merck met with friends in Atlanta, and decided to combine VARIVAX® with the MMR vaccine. The new vaccine MMRV was licensed in 2005 and marketed under the name PROQUAD®. I thought the name was as strange as the idea. [ii]

In early 2008, the FDA announced that the incidence of febrile seizures had increased with the use of PROQUAD® at age 12-15 months and that some reports of encephalitis following vaccination had been filed. [iii]  The Agency then immediately explained that this did not mean that the encephalitis was caused by the vaccine, a standard argument with vaccine adverse events. If one takes an arthritis or an anti-diabetic drug and gets a reaction, the drug is immediately blamed, the lawyers take over and the company suspends or stops manufacturing the problem drug. On the other hand, if someone has a serious reaction shortly after a vaccination, such as an encephalopathy or encephalitis, it is almost always considered a coincidence. No matter the number of reports of vaccine-related adverse events, the verdict is the same: They are all anecdotal and nothing but unscientific observations by nervous parents.

To deal with the increased risk of febrile seizures following the first dose of PROQUAD® (MMRV), the CDC published a long and hard to understand Morbidity and Mortality Weekly Report (MMWR) [iv] on May 7, 2010 that included the following recommendations:

 ·      The routinely recommended ages for measles, mumps, rubella and varicella vaccination continue to be age 12--15 months for the first dose and age 4--6 years for the second dose.

·       For the first dose of measles, mumps, rubella, and varicella vaccines at age 12--47 months, either measles, mumps, and rubella (MMR) vaccine and varicella vaccine or MMRV vaccine may be used. Providers who are considering administering MMRV vaccine should discuss the benefits and risks of both vaccination options with the parents or caregivers. Unless the parent or caregiver expresses a preference for MMRV vaccine, CDC recommends that MMR vaccine and varicella vaccine should be administered for the first dose in this age group.

·       For the second dose of measles, mumps, rubella, and varicella vaccines at any age (15 months--12 years) and for the first dose at age ≥48 months, use of MMRV vaccine generally is preferred over separate injections of its equivalent component vaccines (i.e., MMR vaccine and varicella vaccine). Considerations should include provider assessment, patient preference, and the potential for adverse events.

·        A personal or family (i.e., sibling or parent) history of seizures of any etiology is a precaution for MMRV vaccination. Children with a personal or family history of seizures of any etiology generally should be vaccinated with MMR vaccine and varicella vaccine.


The 25 page current PROQUAD® product insert [v] dated September 2010, that the doctors and their nurses are supposed to read only includes the following recommendations: 

FOR SUBCUTANEOUS ADMINISTRATION ONLY
Each 0.5-mL dose of ProQuad is administered subcutaneously.
The first dose is usually administered at 12 to 15 months of age but may be given anytime through 12 years of age.
If a second dose of measles, mumps, rubella, and varicella vaccine is needed, ProQuad may be used. This dose is usually administered at 4 to 6 years of age. At least 1 month should elapse between a dose of a measles-containing vaccine such as M-M-R II (measles, mumps, and rubella virus vaccine live) and a dose of ProQuad. At least 3 months should elapse between a dose of varicella-containing vaccine and ProQuad.

The difference between the two sets of recommendations is at the very least concerning.  

After VARIVAX® was introduced, we all expected a decrease in the number of cases of chickenpox among children and an increase in the disease incidence among adults, who were likely to be much sicker. That all happened!

As uptake of VARIVAX® increased, the incidence of chickenpox decreased and by 2002, verified pediatric chicken pox cases had dropped by 85% in certain surveillance sites.  Unfortunately, that brilliant result came with a price: The all important chickenpox immunological boosting that had occurred since time immemorial because of continued exposure to wild-type VZV was quickly disappearing and with it all the protection it provided.

The Australians are well known for adopting new vaccination initiatives rather promptly but for some reason they dragged their feet with the varicella vaccine. The Australian health authorities eventually surrendered, and the vaccine was licensed in 2000. On October 18, 2010, the Medical Journal of Australia, the official journal of the Australian Medical Association published an article conceding that since the introduction of the varicella vaccine in 2000 “…there has been a decrease in varicella cases and a rise in HZ cases in Australian general practice consultations”. [vi]

This was absolutely the first time that I had personally seen or heard that very disturbing fact so bluntly stated. The authors’ statistics were very sobering too: The number of general practice consultations for shingles in Australia had increased by 100% in 10 years from 1.7/1000 consultations in 2000 to 3.4/1000 consultations for the first half of 2010. The increase in shingles-related consultations among patients older than 70 during the same period was simply described as substantial.

The fact that the incidence of shingles had increased after the introduction of VARIVAX® has been known for sometime. It was in fact in 2002 that my good friend Gary S. Goldman, Ph.D., had first warned about the recent sudden increase in the incidence of shingles. Goldman, a quiet, soft-spoken and meticulous scientist remains almost apologetic about his discovery; a flashback seems essential to show its brilliance and importance.

Three Varicella Active Surveillance Projects (VASP) were created to monitor trends of varicella (chickenpox) as VARIVAX® was launched. Dr. Goldman worked in the California VASP, located in Antelope Valley, an area of around 300,000 residents. The project easily confirmed that the incidence of chickenpox (varicella) among children was decreasing. Even though everyone knew that the absence of natural disease was likely to compromise the immune boosting that was essential to suppress shingles (herpes zoster) due to the reactivation of varicella zoster virus, the declaration by Dr. Goldman that cases of shingles were much more numerous than expected was still met with denial. No one apparently wanted to concede that, what was logically expected but shamefully overlooked by the vaccine developers was indeed happening. Dr. Goldman begged the principal investigators to address the problem; instead of thanking and praising him, they fought him all the way, ignoring the evidence.
 
History was repeating itself! This was certainly not the first time that people who had discovered important medical facts were marginalized and persecuted.

It was only after the horse was way out of the barn, that surveillance sites started monitoring shingles trends, some five years after the varicella vaccine had been introduced.

Even then, the pro-vaccine forces still remained in solid denial and persistently downgraded the risk; after all, “their serious disease called chickenpox that had killed people” had been wiped out. So what if there was some “collateral damage”.

True to form, the CDC is still not mentioning shingles as a complication of chickenpox vaccination. On October 23, 2010, I reviewed the current Vaccine Information Statement (VIS) for VARIVAX®, [vii] the official information pamphlet that a parent is supposed to read before signing the permission slip allowing the administration of the vaccine.

The document, dated 3/13/2008 only stated that: “A person who has had chickenpox can get a painful rash called shingles years later”. It also still asserts that before the vaccine, about 11,000 people were hospitalized and about 100 died each year in the United States, as a result of chickenpox."

It did not say that the vaccine can double the incidence of shingles among contacts and it certainly did not say how frequently people all over the United States now suffered from the complication.  Nor did it allude to the vastly under-represented 45,000 + chickenpox vaccine-associated reactions so far reported to VAERS.

The “11,000 hospitalizations” attributed to chickenpox are impossible to confirm or deny. What is easier to do is to compare them with other inflated CDC statistics such as influeza-associated hospitalizations [viii] that averaged over 200,000 per year during the 1990s with individual seasons ranging from a low of 157,911 in 1990-91 to a high of 430,960 in 1997-98.

According to information published by the CDC, varicella was the underlying cause of death on average of around 43 children aged less than 15 years, each year from 1990 to 1994, just before VARIVAX® was introduced. [ix] Because the vaccine is primarily intended for children, wouldn’t it have been more honest for the CDC to just mention the number of pediatric deaths in its Vaccine Information Statement instead of inflating the statistics to include the approximately 100 children plus adult deaths. In any case, to help put things in perspective, 82 individuals were killed by lightning strikes, [x] on average, each year from 1980 through 1995 (range: 53-100).

Is VARIVAX® still very effective?

In the early years of administration of the vaccine, immunity of vaccinated individuals was still being boosted by other children with wild type varicella. Because of that exogenous boosting, the reports on varicella vaccine efficacy were biased upwards, with levels above 90% sometimes reported. When exogenous boosting became rare in most communities after 2000,varicella vaccine efficacy declined in certain areas to under 60%.[xi]

According to a 2004 report by the CDC and the Oregon Department of Human Services about a chickenpox outbreak in a highly vaccinated pediatric population,[xii] “Of 422 students, 218 (52%)had no prior chickenpox. Of these, 211 (97%) had been vaccinated before the outbreak. Twenty-one cases occurred in 9 of 16 classrooms. In these 9 classrooms, 18 of 152 (12%) vaccinated students developed chickenpox, compared with 3 of 7 (43%) unvaccinated students. Vaccine effectiveness was 72% (95% confidence interval: 3%–87%)."

What did Merck do?

Responding to the waves of Shingles nationwide and well immune (if you forgive the pun) from litigation because of the National Vaccine Injury Compensation Program, Merck did again what was best for Merck: It invented ZOSTAVAX® to boost the immune system of adults and help suppress or postpone the onset of shingles .That vaccine, essentially a much stronger VARIVAX®, is effective in preventing shingles in about 50% of those individuals receiving it, according to the CDC’s Vaccine Information Statement [xiii] published 10/6/2009.

A single dose is recommended but those in the know quickly add that “it is possible a second dose will be recommended in the future.” Why not?
 
If one considers that VARIVAX® doubled the incidence of shingles in the United States and that ZOSTAVAX® can only prevent 50% of the augmented cases, then the U.S. Government and the good people of this country who paid millions for these achievements got NOTHING for their money, except pain and grief.

According to the CDC October 6, 2010 vaccine price list, [xiv] a single dose of ZOSTAVAX® costs doctors $161.50 and costs the CDC $116.70.

Merck’s chickenpox vaccine had truly become for shareholders the gift that keeps on giving.

For the rest of us, it has just afflicted us with more shingles and with the increased risk of getting chickenpox as adults, when the disease is usually much more serious.

What the varicella vaccination program did to the U.S. Economy was no less unfortunate. Originally, one dose of varicella vaccine was supposed to provide lifetime immunity and supposedly save an estimated $70 million per year--primarily in societal costs associated with a parent staying home from work to care for a child with chickenpox. Instead, the present epidemic of shingles and complications has caused a surcharge of several hundred million dollars that no one anticipated. Added to that is the cost of the now required second dose of VARIVAX®, also a non-anticipated expenditure.
 
It has been proposed that around 25% of medical costs of VZV disease are due to chickenpox and 75% are due to shingles. A relatively small increase in shingles cases can therefore quickly offset any cost-benefit previously expected from universal chickenpox vaccination.

It is interesting that pediatricians, who were now administering VARIVAX® because it was recommended and in places required, had quite a bit to lose …personally.

There was a little secret we had known for sometime but did not discuss too much, may be to ward off the evil eye: We pediatricians, as a group, were less likely than others to get shingles as we aged. 

In 1998, Solomon, Kaporis et al [xv], State University of New York Health Science Center, Brooklyn confirmed that fact statistically… at last. They conducted a study of physicians and found that pediatricians, because they were constantly exposed to Varicella-Zoster Virus, had distinctly lower rates of shingles than psychiatrists who were rarely exposed to the virus and the disease in their practice.

Obviously that is now changing and the thought is depressing!


Shingles, the clinical picture

Some prevalence reviews suggest that women may be more susceptible to shingles than men.

Usually the first manifestation of the disease is pain that can be severe and may represent early on a diagnostic challenge. Many sufferers have been needlessly exposed to X-rays and even CT-scans before the typical rash appeared and the diagnosis became evident.

The rash starts as a crop of contiguous red blind pimples in a dermatome, the area of skin where sensations from a single nerve root in the spinal cord ultimately end.  As new crops develop, the previous lesions start blistering then become pustular and ultimately crust over.

The skin eruption is painful and itchy and can involve any dermatome and sometimes more than one. The rash, often in linear bands, very rarely crosses the midline and is most commonly located on the side of the torso, affecting a nerve root between the third thoracic and the third lumbar roots.

Ophthalmic Zoster affects the distribution area of the ophthalmic branch of the trigeminal nerve, a truly scary presentation.  Other sites such as the face are more rarely involved.

Postherpetic neuralgia is the most dreaded complication of the disease. It is essentially an excruciating and almost unbearable constant burning and tingling pain that follows the rash and may last for weeks, months or longer.

In the debilitated elderly patients the blisters may be very deep and may result in severe scarring. Around 5% of the affected elderly develop muscle weakness.

Early treatment of shingles – within 72 hours of the onset of the rash – with antiviral drugs such as Acyclovir can shorten viral replication and reduce complications. Success has also been achieved recently with the use of intravenous vitamin C.[xvi]  Large scale studies are needed to confirm the findings. Oral vitamin C has been used by some.[xvii]

Anticonvulsants have been used for the symptomatic treatment of postherpetic neuralgia; Neurontin (Gabapentin) in particular appears to have had more success than others. Antidepressants help sometimes. Recently, Lyrica (Pregabalin) has been tried with good results. All these medications require attentive medical supervision.

Over-the-counter painkillers are helpful in mild cases of neuralgia. More often, physicians have to resort to opioids that carry a distinct risk of addiction.

Application of anesthetic creams for local relief is another option for those patients who are reluctant to take drugs.


Thoughts and Reflections

Twenty-first century mainstream medical professionals insist that a vaccine is needed for every acute illness. However, until and unless we do studies comparing the vaccinated to the never-vaccinated, we will never know what is really best for us and for our children.

Honest efforts to study both the long and short-term effects of each vaccination are urgently needed otherwise we are fooling ourselves and just whistling in the dark when we enumerate the alleged benefits of a vaccination. 

In years past, people felt that children were actually stronger and healthier after they recovered from certain contagious diseases. At least one California study seems to support that old belief.

Glioma is an aggressive malignant tumor of the nervous system. Wrensch, Weinberg et al conducted a large adult glioma study in the San Francisco Bay Area from 1997 to 2000 and evaluated associations of immunoglobulin G antibodies to varicella-zoster virus and three other herpesviruses among 229 adults with the disease and 289 controls. They found that patients with glioma were less likely to report a history of chickenpox than controls. Testing also revealed an inverse association with anti-varicella-zoster virus immunoglobulin G, more so in glioblastoma multiforme cases, a subclass. In the case of chicken pox, could we have traded a nuisance of an illness for brain tumors or whatever else may be lurking, unexamined and/or ignored?


Conclusion

Prior to the introduction of the universal varicella vaccination program in the United States, almost 95% of adults experienced natural chickenpox, usually as school age children. These cases were usually benign and resulted in long term immunity because of constant boosting due to repeated exposures to other children and adults with the disease.

This large reservoir of individuals having long term immunity has been seriously compromised by the mass vaccination of children that provides at best 70 to 90% immunity. The vaccine-acquired immunity is of unknown duration and only causes the shifting of chickenpox to the more vulnerable adults.  To arrive to the bottom line, one needs to now add the adverse effects of the required two doses of chickenpox vaccine and the distinct potential for increased risk of shingles for an estimated 30 to 50 years among adults.

One must also keep in mind that regardless of the number of boosters, the acquired immunity from vaccination will never equal the strong constantly-boosted natural immunity we all had in the past, before the Universal Varicella Vaccination program was launched.

Varicella vaccination was a mistake.

Mandating it as a universal vaccination program for every child was an even bigger mistake.


References

[vi] Grant KA, Carville KS, Kelly HA. Evidence of increasing frequency of herpes zoster management in Australian general practice since the introduction of a varicella vaccine. Med J Aust. 2010 Oct 18;193(8):483

[xi] Goldman GS. Universal varicella vaccination: Efficacy trends and effect on herpes-zoster. International Journal of Toxicology, 2005 July-Aug.;24(4):205–13.]

[xv] Solomon BA, Kaporis AG, Glass AT, Simon SI, Baldwin HE. Lasting immunity to varicella in doctors study (L.I.V.I.D. study). J Am Acad Dermatol. 1998 May;38(5 Pt 1):763-5).

[xvii] http://www.orthomolecular.org/resources/omns/v01n05.shtml  Accessed 10/23/10

Immunity-related Literature

 Arvin AM, Koropchak CM, Wittek AE. Immunologic evidence of reinfection with varicella-zoster virus. J Infect Dis. 1983 Aug;148(2):200-5.

Resistance to reinfection with varicella-zoster virus (VZV) was evaluated in immune adults who had household exposure to varicella. Sixty-four percent of 25 adults exposed to varicella had a fourfold or greater rise in IgG antibody to VZV or had a high initial IgG antibody titer to VZV that declined by fourfold. ... The increase in immunity to VZV in many immune subjects exposed to VZV suggests the occurrence of subclinical reinfection.

PMID: 6310001

 Arvin AM. Cell-mediated immunity to varicella-zoster virus. J Infect Dis. 1992 Aug;166 Suppl

1:S35-41)

 Natural varicella-zoster virus (VZV) infection and immunization with live attenuated varicella vaccine elicits T lymphocytes that recognize VZV glycoproteins, gpI-V, and the immediate early/tegument protein, the product of gene 62 (IE62). Proliferation or cytotoxicity assays, done under limiting dilution conditions to estimate responder cell frequencies, indicate no preferential recognition of VZV proteins by human T cells. Analysis of the primary cytotoxic T lymphocyte (CTL) response after vaccination demonstrates that both gpI and IE62 are targets of the early response. CD4(+)- and CD8(+)-mediated CTL recognition of these viral proteins can be detected with natural and vaccine-induced immunity. Responder cell frequencies for protein-specific T cell proliferation and CTL function are generally comparable in subjects with natural and vaccine-acquired immunity to VZV. Exogenous reexposure to VZV results in enhanced T cell proliferation and may be an important mechanism for maintaining virus-specific cellular immunity. Providing exogenous reexposure by giving varicella vaccine to individuals who have preexisting natural immunity markedly increases the responder cell frequencies of T cells that proliferate in response to VZV antigen and the numbers of circulating CTL that recognize VZV proteins.

PMID: 1320649

 Terada K, Hiraga Y, Kawano S, Kataoka N. Incidence of herpes zoster in pediatricians and history of reexposure to varicella-zoster virus in patients with herpes zoster. Kansenshogaku Zasshi. 1995 Aug;69(8):908-12 ) [Article in Japanese]  

We found that pediatricians have enhanced specific cellular immunity to varicella-zoster virus (VZV) compared with the general population, which may be due to reexposure to VZV from children with chickenpox. There have been some reported that the varicella vaccine enhance the specific cellular immunity. To estimate the efficacy of varicella vaccine for protection against herpes zoster in the elderly, we investigated the incidence of herpes zoster in 500 pediatricians and family practitioners with their fifties and sixties, and history of reexposure to VZV in 61 patients with herpes zoster by questionnaires retrospectively. Thirty four of 352 pediatricians had a past history of herpes zoster. The incidence per 100,000 person-years of herpes zoster was 65.2 in those in their fifties and 158.2 in those in their sixties, which are 1/2 to 1/8 of other reports regarding the general population. Among 61 immunocompetent patients with herpes zoster, only 4 patients (6.6%) had the chance for reexpose to VZV before their herpes zoster. Only 7 (17.5%) of the 40 patients older than 50 years of age lived with their children less than 14 years of age. Twenty-three (57.5%) of them lived without their children and grandchildren. They are thought to be less chance to reexpose to VZV through children. We may think that the booster effect by reexposure to VZV plays an important role to prevent herpes zoster. Therefore, we can speculate that the varicella vaccine may protect against herpes zoster in the elderly by the enhanced specific cellular immunity due to the booster effect.

PMID: 7594784

 Gershon AA, LaRussa P, Steinberg S, Mervish N, Lo SH, Meier P. The protective effect of immunologic boosting against zoster: an analysis in leukemic children who were vaccinated against chickenpox. J Infect Dis. 1996 Feb;173(2):450-3

 Whether reexposure of varicella-immune persons to varicella-zoster virus would protect against or predispose to development of zoster was analyzed. The rate of zoster in 511 leukemic recipients of varicella vaccine who had 1 or > 1 dose of varicella vaccine and in those who did or did not have a household exposure to varicella was determined. A Kaplan-Meier life-table analysis revealed that the incidence of zoster was lower in those given > 1 dose of vaccine (P < .05). A Cox proportional hazards analysis showed that both household exposure to varicella and receipt of > 1 dose of vaccine were highly protective (P < .01) against zoster. Thus, the risk of zoster is decreased by reexposure to varicella-zoster virus, either by vaccination or by close exposure to varicella.

PMID: 8568309

 Spingarn RW, Benjamin JA, Meissner HC. Universal vaccination against varicella N Engl J Med, 1998 Mar 5; 338(10):683) [Correspondence].

 To the Editor: Historically, chickenpox has been largely a benign disease affecting predominantly preschool and school-aged children. Times are changing: in Massachusetts, children enrolled in day-care programs will soon be required to be vaccinated against varicella (or have evidence of having had the disease). Although it is generally held that immunizing children is axiomatic for public health, vaccinating all children against chickenpox is a bad idea. It is unknown whether long-term immunity to varicella arises from an attack of the disease in childhood or from the virus's repeatedly (and naturally) boosting immunity because it is maintained in our communities. ... Yet policies of universal vaccination of children [against chickenpox] will serve, over time, to eradicate most, but not all, naturally occurring [chickenpox] and its immeasurable booster effect.

PMID: 9490383

 

  Schuette MC, Hethcote HW. Modeling the Effects of Varicella Vaccination Programs on the Incidence of Chickenpox and Shingles. Bulletin of Mathematical Biology 1999;61:1031-64)

Two possible dangers of an extensive varicella vaccination program are more varicella (chickenpox) cases in adults, when the complications rates are higher, and an increase in cases of zoster (shingles). Here an age-structured epidemiologic-demographic model with vaccination is developed for varicella and zoster. Parameters are estimated from epidemiological data. This mathematical and computer simulation model is used to evaluate the effects of varicella vaccination programs. Although the age distribution of varicella cases does shift in the simulations, this does not seem to be a danger because many of the adult cases occur after vaccine-induced immunity wanes, so they are mild varicella cases with fewer complications. In the simulations, zoster incidence increases in the first three decades after initiation of a vaccination program, because people who had varicella in childhood age without boosting, but then it decreases. Thus the simulations validate the second danger of more zoster cases.

 Krause PR. Evidence for frequent reactivation of the Oka varicella vaccine strain in healthy vaccinees. . Arch Virol Suppl 2001;(17):7-15)

 Serum antibody levels and infection rates were followed for 4 years in 4,631 children immunized with the recently licensed Oka strain varicella vaccine. Anti-VZV titers declined over time in high-responder subjects, but rose in vaccinees with low titers. Among subjects with low anti-VZV titers, the frequency of clinical sequelae and immunological boosting significantly exceeded the 13%/yr rate of exposure to wild type varicella. These findings indicate that the Oka strain of VZV persisted in vivo, and reactivated as serum antibody titers declined after vaccination. This mechanism may improve vaccine-associated long-term immunity. Pre-licensure clinical studies showed that mean serum anti-VZV levels among vaccinees continued to increase with time after vaccination. This was attributed to immunologic boosting caused by exposure to wild-type VZV in the community.

PMID: 11339552


 Thomas SL, Wheeler JG, Hall AJ. Contacts with varicella or with children and protection against herpes zoster in adults: a case-control study. Lancet. 2002 Aug 31;360(9334):678-82)

 BACKGROUND: Whether exogenous exposure to varicella-zoster-virus protects individuals with latent varicella-zoster virus infection against herpes zoster by boosting immunity is not known. To test the hypothesis that contacts with children increase exposure to varicella zoster virus and protect latently infected adults against zoster, we did a case-control study in south London, UK. ... INTERPRETATION: Re-exposure to varicella-zoster virus via contact with children seems to protect latently infected individuals against zoster. Reduction of childhood varicella by vaccination might lead to increased incidence of adult zoster. Vaccination of the elderly (if effective) should be considered in countries with childhood varicella vaccination programmes.

PMID: 12241874

   Brisson M, Gay NJ, Edmunds WJ, Andrews NJ. Exposure to varicella boosts immunity to herpes-zoster: implications for mass vaccination against chickenpox.

Vaccine. 2002 Jun 7;20(19-20):2500-7

 We present data to confirm that exposure to varicella boosts immunity to herpes-zoster. We show that exposure to varicella is greater in adults living with children and that this exposure is highly protective against zoster (Incidence ratio=0.75, 95% CI, 0.63-0.89). The data is used to parameterise a mathematical model of varicella zoster virus (VZV) transmission that captures differences in exposure to varicella in adults living with and without children. Under the 'best-fit' model, exposure to varicella is estimated to boost cell-mediated immunity for an average of 20 years (95% CI, 7-41years). Mass varicella vaccination is expected to cause a major epidemic of herpes-zoster, affecting more than 50% of those aged 10- 44 years at the introduction of vaccination.

PMID: 12057605

  Brisson M, Edmunds WJ. Varicella vaccination in England and Wales: cost-utility analysis. Arch Dis Child. 2003 Oct;88(10):862-9

 AIMS: To assess the cost-effectiveness of varicella vaccination, taking into account its impact on zoster. METHODS: An age structured transmission dynamic model was used to predict the future incidence of varicella and zoster. Data from national and sentinel surveillance systems were used to estimate age specific physician consultation, hospitalisation, and mortality rates. Unit costs, taken from standard sources, were applied to the predicted health outcomes. RESULTS: In England and Wales, the annual burden of VZV related disease is substantial, with an estimated 651,000 cases of varicella and 189,000 cases of zoster, resulting in approximately 18,000 QALYs lost. The model predicts that although the overall burden of varicella will significantly be reduced following mass infant vaccination, these benefits will be offset by a significant rise in zoster morbidity. Under base case assumptions, infant vaccination is estimated to produce an overall loss of 54,000 discounted QALYs over 80 years and to result in a net cost from the health provider (NHS) and the societal perspectives. These results rest heavily on the impact of vaccination on zoster….Conclusion:  Routine infant varicella vaccination is unlikely to be cost-effective and may produce an increase in overall morbidity. Adolescent vaccination is the safest and most cost-effective strategy, but has the least overall impact on varicella.

PMID: 14500303


 
Thomas SL, Hall AJ. What does epidemiology tell us about risk factors for herpes zoster? Lancet Infect Dis, 2004 Jan.; 4(1):26-33

 Reactivation of latent varicella zoster virus as herpes zoster is thought to result from waning of specific cell-mediated immunity, but little is known about its determinants in individuals with no underlying immuno-suppression. We systematically reviewed studies of zoster epidemiology in adults and analysed data from a large morbidity study to identify factors that might be modulated to reduce the risk of zoster. Annual zoster incidence in population-based studies varied from 3.6-14.2/10(3) in the oldest individuals. Risk factors identified in analytical studies that could explain this variation included age, sex, ethnicity, genetic susceptibility, exogenous boosting of immunity from varicella contacts, underlying cell-mediated immune disorders, mechanical trauma, psychological stress, and immunotoxin exposure. Our review highlights the lack of information about risk factors for zoster. We suggest areas of research that could lead to interventions to limit the incidence of zoster. Such research might also help to identify risk factors for age-related immune decline.

PMID: 14720565

  Outbreak of varicella among vaccinated children--Michigan, 2003.

MMWR Morb Mortal Wkly Rep. 2004 May 14;53(18):389-92.

Centers for Disease Control and Prevention (CDC).

 On November 18, 2003, the Oakland County Health Division alerted the Michigan Department of Community Health (MDCH) to a varicella (chicken pox) outbreak in a kindergarten-third grade elementary school. On December 11, MDCH and Oakland County public health epidemiologists, with the technical assistance of CDC, conducted a retrospective cohort study to describe the outbreak, determine varicella vaccine effectiveness (VE), and examine risk factors for breakthrough disease (i.e., varicella occurring >42 days after vaccination). This report summarizes the results of that study, which indicated that 1) transmission of varicella was sustained at the school for nearly 1 month despite high vaccination coverage, 2) vaccinated patients had substantially milder disease (<50 lesions), and 3) a period of > or =4 years since vaccination was a risk factor for breakthrough disease.

 W. Katherine Yih, Daniel R. Brooks, Susan M. Lett, Aisha O. Jumaan, Zi Zhang, Karen M. Clements, Jane F. Seward. The incidence of varicella and herpes zoster in Massachusetts as measured by the Behavioral Risk Factor Surveillance System (BRFSS) during a period of increasing varicella vaccine coverage, 1998-2003.

BMC Public Health. 2005 Jun 16;5(1):68

 BACKGROUND: The authors sought to monitor the impact of widespread varicella vaccination on the epidemiology of varicella and herpes zoster. While varicella incidence would be expected to decrease, mathematical models predict an initial increase in herpes zoster incidence if re-exposure to varicella protects against reactivation of the varicella zoster virus. METHODS: In 1998-2003, as varicella vaccine uptake increased, incidence of varicella and herpes zoster in Massachusetts was monitored using the random-digit-dial Behavioral Risk Factor Surveillance System. RESULTS: Between 1998 and 2003, varicella incidence declined from 16.5/1,000 to 3.5/1,000 (79%) overall with >65% decreases for all age groups except adults (27% decrease). Age-standardized estimates of overall herpes zoster occurrence increased from 2.77/1,000 to 5.25/1,000 (90%) in the period 1999-2003, and the trend in both crude and adjusted rates was highly significant (p<0.001). Annual age-specific rates were somewhat unstable, but all increased, and the trend was significant for the 25-44 year and 65+ year age groups. CONCLUSIONS: As varicella vaccine coverage in children increased, the incidence of varicella decreased and the occurrence of herpes zoster increased. If the observed increase in herpes zoster incidence is real, widespread vaccination of children is only one of several possible explanations. Further studies are needed to understand secular trends in herpes zoster before and after use of varicella vaccine in the United States and other countries.

PMID: 15960856

 Volpi A. Editorial:  varicella immunization and herpes zoster. Herpes: the journal of the IHMF,

2005 Dec; 12(3):59

 Boosting VZV immunity can protect against zoster: re-exposure to VZV via contact with children protects latently infected individuals. Memory CD4 and CD8 cells that recognize VZV proteins are readily detectable in younger adults, in whom zoster is relatively rare, although the capacity of peripheral-blood T-cells in those who are latently infected with VZV appears to diminish with age.... [Cellular immunity] ... appears more likely to be a consequence of periodic boosting on exposure to VZV or zoster... The decreasing incidence of VZV following universal childhood vaccination is of concern, because a reduced circulation of wild-type VZV could lead to more cases of zoster in older people, whose immunity is no longer being boosted by exposure to children with primary infection.

PMID: 16393520

 Abarca VK. Varicella Vaccine. Rev Chilena Infectol. 2006 Mar;23(1):56-9

 Varicella and herpes zoster represent a significant public health problem. Safe and highly effective varicella vaccines against severe and moderate varicella are currently available. Vaccine efficacy is lower and more variable against mild disease and several risk factors have been associated with mild breakthrough disease. Experts are currently discussing the need for a second vaccine dose. Universal varicella vaccination has been highly effective in reducing morbidity and hospitalizations due to varicella, a strategy that has proven to be cost effective in many regions when the societal-perspective is considered in the analysis. Recent data suggests that varicella vaccination may be associated with an increased incidence of herpes zoster in the elderly. Immunity conferred by varicella vaccination seems to be long lasting but a continued evaluation is needed in order to asses the effect of the changing epidemiology associated with universal immunization.

PMID: 16462966

 Welsby PD.Chickenpox, chickenpox vaccination and shingles. Postgrad Med J. 2006 May;82(967):351-352

 “We know that exposure to chickenpox can significantly prevent or delay shingles (by exogenous boosting of immunity)… Having a child in the household reduced the risk of shingles for about 20 years…”

PMID: 16679476

Chaves SS, Gargiullo P, Zhang JX, Civen R, Guris D, Mascola L, Seward JF.

Loss of Vaccine-Induced Immunity to Varicella Over Time NEJM 2007 Mar 15;356(11):1121-9)

 Background: The introduction of universal varicella vaccination in 1995 has substantially reduced varicella-related morbidity and mortality in the United States. However, it remains unclear whether vaccine-induced immunity wanes over time, a condition that may result in increased susceptibility later in life, when the risk of serious complications may be greater than in childhood.

Methods: We examined 10 years (1995 to 2004) of active surveillance data from a sentinel population of 350,000 subjects to determine whether the severity and incidence of breakthrough varicella (with an onset of rash >42 days after vaccination) increased with the time since vaccination. We used multivariate logistic regression to adjust for the year of disease onset (calendar year) and the subject's age at both disease onset and vaccination.

Results: A total of 11,356 subjects were reported to have varicella during the surveillance period, of whom 1080 (9.5%) had breakthrough disease. Children between the ages of 8 and 12 years who had been vaccinated at least 5 years previously were significantly more likely to have moderate or severe disease than were those who had been vaccinated less than 5 years previously (risk ratio, 2.6; 95% confidence interval [CI], 1.2 to 5.8). The annual rate of breakthrough varicella significantly increased with the time since vaccination, from 1.6 cases per 1000 person-years (95% CI, 1.2 to 2.0) within 1 year after vaccination to 9.0 per 1000 person-years (95% CI, 6.9 to 11.7) at 5 years and 58.2 per 1000 person-years (95% CI, 36.0 to 94.0) at 9 years.

Conclusions A second dose of varicella vaccine, now recommended for all children, could improve protection from both primary vaccine failure and waning vaccine-induced immunity.

PMID: 17360990

 Quan D, Cohrs RJ, Mahalingam R, Gilden DH. Prevention of shingles: safety and efficacy of live zoster vaccine. Ther Clin Risk Manag. 2007 Aug;3(4):633-9

 Primary infection with varicella zoster virus (VZV) causes chickenpox (varicella) after which virus becomes latent in cranial nerve, dorsal root and autonomic ganglia along the entire neuraxis. Virus may later reactivate, causing shingles (zoster), characterized by pain and rash restricted to 1-3 dermatomes. More than 40% of zoster patients over age 60 develop postherpetic neuralgia (PHN), pain that persists for months to years. The socioeconomic impact of primary varicella infection has been lessened by introduction of VZV vaccine for children. However, the effect of childhood vaccination on the incidence of zoster is unknown. Virus reactivation correlates with waning cell-mediated immunity (CMI) to VZV with normal aging. Adults exposed to children with varicella may have a boost in CMI to VZV. For at least several more decades, the incidence of zoster may increase as the elderly population grows. The anticipated increase in zoster burden of illness in future decades was a major impetus for the Shingles Prevention Study, a prospective, double-blind, placebo-controlled trial of attenuated VZV vaccine to prevent zoster in older adults. This review discusses clinical and virological aspects of zoster and its complications, current treatment options, and VZV vaccine development along with its future role in disease prevention.

PMID: 18472986

Yawn BP, Saddier P, Wollan PC, St Sauver JL, Kurland MJ, Sy LS. A Population-Based Study of the Incidence and Complication Rates of Herpes Zoster Before Zoster Vaccine Introduction. Mayo Clin Proc. 2007 Nov;82(11):1341-9.

 RESULTS: A total of 1669 adult residents with a confirmed diagnosis of HZ were identified between January 1, 1996, and December 31, 2001. Most (92%) of these patients were immunocompetent and 60% were women. When adjusted to the US adult population, the incidence of HZ was 3.6 per 1000 person-years (95% confidence interval, 3.4-3.7), with a temporal increase from 3.2 to 4.1 per 1000 person-years from 1996 to 2001.

PMID: 17976353

  Jardine A, Conaty SJ, Vally H. Herpes zoster in Australia: evidence of increase in incidence in adults attributable to varicella immunization? Epidemiol Infect. 2010 Aug 23:1-8.

SUMMARY:  Rates of herpes zoster (HZ) hospitalizations, antiviral prescriptions, and New South Wales emergency-department presentations for age groups <20, 20-39, 40-59 and 60 years were investigated. Trends were analysed using Poisson regression to determine if rates increased following funding of varicella immunization in Australia in November 2005. The regression analysis revealed significantly increasing trends of between 2% and 6% per year in both antiviral prescriptions and emergency-department presentations in all except the <20 years age group. When considered together, the differential changes in rates observed by age group provides preliminary evidence to indicate that HZ incidence is increasing in adults aged >20 years. However, it is not possible to attribute the increasing trends in HZ observed directly to the varicella immunization programme, and continued monitoring and analyses of data for a longer duration, both pre- and post-vaccine introduction, is required.

PMID: 20727248


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Dr. Goldman's assistance was very much appreciated.

F. Edward Yazbak, MD, FAAP
Falmouth, Massachusetts