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Measles, Haemophilus influenzae Type B, Varicella: Pre- and Postvaccine Epidemiology in the United States

  • Authors: Authors: Gregory Poland, MD, Robert Jacobson, MD, and David Phelan, MD
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Target Audience and Goal Statement

This activity is intended for infectious disease specialists, primary care physicians and family medicine physicians.

The goal of this activity is to provide a comprehensive review of the epidemiology of Measles, HIB and Varicella pre- and post- introduction of their respective vaccines.

On completion of this continuing medical education offering, participants will be able to:

  1. Describe the epidemiology of measles, HIB and varicella prior to the introduction of their respective vaccines.

  2. Compare the epidemiology of measles, HIB and varicella after the introduction of their respective vaccines.

  3. Discuss the efficacy of the measles, HIB and varicella vaccines.

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Measles, Haemophilus influenzae Type B, Varicella: Pre- and Postvaccine Epidemiology in the United States


Varicella Vaccine: A Work in Progress


Before the introduction of the vaccine in the United States in 1995, the primary form of varicella zoster virus (VZV) infection, chicken pox, was a universal rite of passage for children in temperate countries such as the United States.

Natural varicella disease usually confers lifelong immunity, but secondary, symptomatic infections have been documented.[85] Asymptomatic reinfections are common, as evidenced by immunologic correlates as well as by polymerase chain reaction-based assays.[86,87] It is unknown what role these subclinical infections play in sustaining an individual's immunity, and it is suspected that universal childhood vaccination will eliminate the majority of these subclinical infections.

Zoster represents a recrudescence of the dormant VZV that enters a chronic latent phase following infection with varicella.[88] It is estimated that 300,000 cases of zoster occur each year in the United States, and the incidence increases with age.[88] Most persons who contract zoster suffer only 1 bout of zoster. Only 5% of cases each year represent a recurrence.[88] By 80 years of age, 1 out of 7 persons will have had zoster. Direct contact with zoster lesions can transmit the VZV and result in new cases of varicella among susceptible persons. This means of transmission, however, is thought unimportant to the incidence of varicella.[88]

Compared with the measles and Haemophilus influenzae type b vaccines, the varicella vaccine is relatively new and this has resulted in lower coverage rates. One concern about this vaccine is that if not quite enough children receive the varicella vaccine and if a significant fraction of the children who do receive it suffer waning immunity as they age, will many individuals suffer varicella as adults -- with the typically more severe rates of morbidity and mortality?


The Disease

Varicella is a febrile illness characterized by a generalized, pruritic, vesicular rash, consisting of 250 to 500 lesions usually involving the face, scalp, and trunk.[88,89] Complications include bacterial infection of the skin, swelling of the brain, and pneumonia. The disease is more severe and results in more complications in children 13 or older and adults. The prodromal fever appears before the rash, which appears in crops with older lesions crusting in the same areas where new ones are forming.

Zoster represents a recrudescence of the infection occurring usually decades after the primary infection of chickenpox.[88,89] Usually only 1 nerve root is affected, resulting in a painful, vesicular rash involving 1 to 3 sensory dermatomes and lasting for 1 week.

Varicella disease has some striking characteristics.[88-93] Varicella is limited to humans, and there are no known animal reservoirs or vectors. Infection with the VZV occurs through the respiratory tract and is spread primarily person-to-person through direct contact with infected respiratory secretions. The virus is highly contagious, and infected persons are contagious from 1 to 2 days before the rash appears until all the lesions develop crust -- usually 4 to 5 days after the rash appears. People are most contagious in the 2 days preceding and the 2 days following onset of the rash. The incubation period typically is 14 to 16 days, but can be as short as 11 days or as long as 20 days. Infection will develop in 85% to 95% of susceptible household contacts.

Varicella is less prevalent among children in tropical climates, resulting in more disease among adults. Varicella in adults is associated with higher morbidity and mortality. The decreased incidence of childhood varicella in tropical climates is unexplained.[90,94] Perhaps 50% of young adults living in tropical regions have not had varicella. In temperate climates, the disease occurs most commonly in late winter and early spring, but the seasonal changes that occur in temperate climates are absent in tropical climates. While the heat, humidity, and absence of indoor crowding during winter might explain the different pattern in tropical climates, this variation between climates is not seen with measles, for example.


Varicella Epidemiology: Prevaccine Era

Before the vaccine became available, more than 90% of individuals were infected by 14 years of age; the annual incidence rate was estimated to approximate the birth cohort.[89,90,95] In a prevaccine study of 8,000 youths aged 5 to 19 years at Kaiser Permanente Medical Care Program, Northern California, the annual incidence of varicella was 10.3% in 5- to 9-year-olds, 1.9% in 10- to 14-year-olds, and 1.2% in 15- to 19-year-olds.[96]

Nonetheless, data from both the United States and the United Kingdom indicate an unexplained shift in the age-distribution of cases over the last 20 years, which predates the introduction of the vaccine.[95] In England and Wales, the incidence of reported cases in persons older than 14 years of age doubled between 1967 and 1970 and 1991 and 1995, as did the death rate.[95] While similar incidence rates are unavailable in the United States, the hospital admission rates among Army personnel increased 4-fold between 1980 and 1988, and increased 18-fold between 1975 and 1988 among Navy personnel.[95] Possible explanations include the emigration of susceptible individuals from tropical climates to temperate climates.


Varicella Epidemiology: Postvaccine Era

Varicella epidemiology data in the postvaccine era are limited. In a study of 11 daycare centers in North Carolina, the rate of vaccine coverage increased from 4% in 1995 to 63% in December 1999.[97] During that same period, the incidence of disease decreased from 17 cases/1000 person-months to 2 cases/1000 person-months.

One of the most significant, persistent concerns about the routine use of the vaccine in children is that -- with incomplete vaccine coverage of children, incomplete generation of protective efficacy among recipients, and the potential for waning immunity from the lack of subclinical boosting -- the disease incidence will shift from children to adults with the resultant increase in morbidity, complications, and mortality seen with adult disease.[98,99] Thus, theoretically, routine vaccination against varicella in children may result in overall worsening health across the population. This phenomenon was observed with the introduction of rubella vaccine in Greece.[100]

Brisson and colleagues[101] created a mathematical model for the effects of routine childhood VZV vaccine that featured an age-structuring to account for the potential for increased transmission with age. A variety of vaccine efficacies, vaccine coverages, and vaccine strategies were investigated, and a sensitivity analysis of important parameters was performed. The model found that mass vaccination of 12-month-olds would reduce the incidence and morbidity of cases, both natural and breakthrough. Mass vaccination reduces overall morbidity as coverage increases despite an increase in the average age of infection and an increase in morbidity with age. Halloran and colleagues[102] have similarly modeled the shifts in age-incidence and mortality resulting from varicella vaccination and have found similar results. Such modeling is reassuring but will require confirmation through careful surveillance in the years to come.


The Economics of Varicella Immunization

In the prevaccine era, the disease resulted in approximately 5 million cases a year. Cost-benefit analyses have shown the vaccine to be cost-effective even if only considering the medical costs.[103] Costs of varicella total one half billion dollars a year in the United States; these include both medical and work-loss costs. Given current measures of efficacy, a program of routine vaccination in childhood in the first 30 years of the program would save approximately $400 million a year on average.


The Vaccine

The US Food and Drug Administration licensed the varicella vaccine (Varivax) in March 1995 for use in persons 12 months of age or older. The ACIP, AAP, and AAFP have recommended routine immunization of children and adolescents. Nationally, in children aged 19 to 35 months, the varicella vaccination rate increased from 25% in 1997 to 67% in 2000.[104]

In contrast to the nearly 100% protection conferred in those with natural infection, immunity from the vaccine is incomplete. About 70% to 85% of recipients develop protective efficacy.[105,106] Fifteen to thirty percent develop varicella when exposed to wild virus, albeit a mild form with less than 35 lesions. A case-control study conducted in New Haven, Connecticut, found the vaccine to be effective, with a measured efficacy rate of 85% (95% CI, 78% to 90%).[105] Against moderately severe or severe disease, the vaccine was 97% effective (95% CI, 93% to 99%).

One study reported a surprisingly high rate of breakthrough varicella among vaccinated children.[107] In this study of 593 healthy Japanese children, the cumulative incidence 7 to 9 years after vaccination was reportedly 159/459, or 34.2%. The study suffered from some limitations. An unreported number of children was vaccinated prior to 12 months of age, when placentally transmitted maternal antibody may block the vaccine. Furthermore, of the 593, only 459, or 77.4%, responded. The breakthrough varicella rate may have been as low as 147/593, or 26.5%. In any event, the overwhelming majority of children suffered only mild disease. One third experienced fever, which lasted only 1 to 2 days in 80%. Sixty percent had fewer than 30 vesicles and papules, and about 12% had about 100 vesicles or papules.

For those who develop immunity from the vaccine, the immunity appears durable. Studies in the Japanese children vaccinated 20 years ago demonstrate persistent protection now as adults.[108,109] While these data are reassuring, the children studied lived during an era of continued wild varicella exposure, and their persistent immunity may have benefited from continued subclinical infection and resultant boosting.

Vaccine-related adverse events include injection site pain and inflammation in approximately 20% of recipients.[89,94] About 3% of children develop a varicella-like rash at the injection site in the first 2 weeks after the vaccination. Four to six percent develop a generalized varicella-like rash averaging 5 maculopapular or vesicular lesions and occurring in the first 3 weeks after vaccination. Fever occurs in 15% of children and 10% of adults in the month and a half following vaccination but most often is attributable to intercurrent illness and not the vaccine.

The risk of transmission from the vaccine itself -- a live attenuated vaccine-- appears to be very low and has been documented in immunocompetent recipients in only 3 cases out of 15 million doses distributed.[89,110,111] In all 3 cases, the disease was mild and without complications. Secondary transmission has only been documented when a vesicular rash developed postvaccination.

Similar to infection with varicella, the vaccine does result in a latent infection. Zoster does occasionally follow vaccination, but fewer than 50 cases have been reported, and not all have been confirmed as being the result of the vaccine virus.[89,112] All cases have been mild and without complications. The rate of zoster in children is estimated to be 18 cases per 100,000 -- one fourth the rate of the 77 cases per 100,000 seen with natural varicella infection.



In summary, the epidemiology of varicella has changed and will continue to change, primarily because of the introduction of routine vaccination of children. The age-distribution of the incidence and morbidity will continue to shift upward. Nonetheless, modeling indicates that the overall balance will be positive, and there will be overall reduction of the incidence and morbidity of this vaccine-preventable disease.