DR. FREED is a professor of pediatrics at the Division of General Pediatrics, University of Michigan, Ann Arbor, and director of the Child Health Evaluation and Research Unit, University of Michigan, Ann Arbor. He is also a member of <i>Contemporary Pedia

Gary L. Freed, MD, MPH

The second in a year-long series of commentary reviewing topics published in

 25 years ago. This month’s article discusses the impact of the varicella vaccine.

Dr. Anne Gershon is currently director of the division of pediatric infectious diseases and professor of pediatrics at Columbia University, New York City. Her research has included epidemiology, diagnosis, immunology, latency, prevention, and treatment of varicella and zoster virus infections. Her studies with varicella vaccine were crucial to its licensure.

 article, Anne A. Gershon, MD, wrote about the likelihood of licensing the varicella vaccine in the US. At the time, the varicella vaccine had been widely used in Japan, mainly to immunize children with underlying malignancies and to halt the nosocomial spread of the disease.

In contrast, Gershon noted at that time, efforts in the US to prevent severe varicella had been directed toward the discovery of an effective method for passive rather than active immunization. This resulted in the development of the varicella-zoster immune globulin (VZIG). However, this did not effectively arrest transmission of the virus on a population-wide basis.

Gershon discussed the differences in opinion among pediatricians about the use of the vaccine in the US. Would the vaccine only be used for those at high risk for developing severe varicella, or would it be used for “normal” children as well? She noted that although most physicians classify varicella as a benign disease, “they and the parents are mindful of the school days lost and the sequelae of natural varicella, such as bacterial superinfections and Reye’s syndrome.”

The article also offered perspectives on the most appropriate time for varicella immunization should it be licensed in the US. Gershon noted that studies were already underway to test the efficacy of the vaccine when administered at the same time as the measles-mumps-rubella (MMR) vaccine. Preliminary data were suggesting “this approach will be successful.” Gershon also posited that only one dose of varicella vaccine “will be sufficient to protect normal children.”

The article was written just prior to the time that several new vaccine recommendations would be released. Trying to predict the future immunization schedule appears to be as difficult now as it was then. Many of the same issues regarding potential new vaccines were on the public health agenda: the potential need for booster doses, the perception of the severity of the disease to be prevented, and the appropriate indications for the vaccine.

On March 17, 1995, ten years after the publication of this article, the Food and Drug Administration  licensed varicella vaccine for use by susceptible individuals 12 months of age and older. The American Academy of Pediatrics recommended that varicella vaccine be added to the childhood immunization schedule in May 1995, and the Advisory Committee on Immunization Practices (ACIP) followed suit in July 1996.

In contrast to Gershon’s expectations, two doses of varicella vaccine ultimately were recommended for children in 2006. This was the result of data that demonstrated that compared with children who received one dose, two-dose vaccine recipients developed a larger proportion of antibody titers that were more likely to protect against breakthrough disease.

 The first dose is recommended at 12 to 15 months of age. As predicted by Gershon, it is usually given at the same time as MMR vaccine. The second dose is recommended at 4 to 6 years, around the same time of the second MMR vaccine (also not recommended back in 1985). It may be given sooner, as long as it is separated from the first dose by at least three months.

The impact of the varicella vaccine on the population has been dramatic, and likely exceeds the expectations of Gershon and her colleagues when the original article was written. Before the introduction of the live attenuated varicella vaccine in 1995, approximately four million cases of varicella occurred annually in the US, resulting in approximately 11,000 hospitalizations and 100 deaths.

Progressively widespread use of varicella vaccine in the US has significantly altered varicella epidemiology. The Centers for Disease Control and Prevention report incidence reductions of approximately 85% from 1990 to 2001. Most importantly, this has resulted in a 75% decrease in varicella-related hospitalizations across the US, as well as a similar decrease in the number of deaths caused by complications of chicken pox.

Gershon would have expected hospitalization rate declines among children who received the vaccine. She likely would not have predicted the interruption of transmission of the virus from vaccinated children to unvaccinated adults, resulting in a decrease in hospitalization among adults as well.

In 1985, cost-effectiveness studies were not commonly performed, and they were not often used to determine whether a specific therapy was recommended for use. Today the economics of health care have markedly changed, and such issues are of great importance. As such, studies of the economic impact of varicella vaccine have been conducted, and have shown a significant positive impact. Varicella-related hospital charges declined from $161 million in 1993 to $66.3 million in 2001 (all 2001 dollars). Among payers, there were inflation-adjusted declines in varicella-related charges related to hospital discharges accrued to Medicaid, private insurance, and “other” payers (including uninsured and self-pay).

A decade of varicella prevention in the US has resulted in a dramatic decline in disease. The next decade will provide the data to help determine the long-term protection provided by the two-dose schedule. ◽


1. Marin M, Meissner HC, Seward JF: Varicella prevention in the United States: a review of successes and challenges. 

 2008;122:e744
2. Zhou F, Harpaz R, Jumaan AO, et al: Impact of varicella vaccination on health care utilization. 

 2005;294:797
3. Davis MM, Patel MS, Gebremariam A: Decline in varicella-related hospitalizations and expenditures for children and adults after introduction of varicella vaccine in the United States. 

Articles

The second in a year-long series of commentary reviewing topics published in Contemporary Pediatrics 25 years ago.

Then and Now: Varicella vaccine

This review provides a brief overview of meningococcal disease, compares the characteristics of MCV4 and MPSV4, describes the indications for using the vaccines, and discusses recently raised concerns about the safety of MCV4.  

Since the implementation of widespread immunization against 

 has become the leading cause of meningitis among children and young adults in this country.

  Other clinical sequelae, such as pneumonia, septicemia without meningitis, occult bacteremia, and focal infections, also can follow infection with 

Symptoms vary somewhat with age. Older adolescents are more likely than infants to have shock and septicemia without meningitis at presentation, and to die.

 occurs by respiratory droplets or direct contact with respiratory secretions (kissing, sharing drinking glasses, mouth-to-mouth resuscitation). Although invasive meningococcal disease draws the most public attention, it is believed that asymptomatic nasopharyngeal colonization with nonencapsulated, low-pathogenicity strains is actually the most common form of infection.

  Colonization is thought to immunize most people; those who do not produce antibodies after colonization are likely still susceptible to future infection.

  The colonization rate, which varies greatly with age, geography, and crowding, may be more than 20% in some populations.

In the US, the highest incidence of invasive meningococcal disease occurs in children younger than 1 year; a second, lower peak of illness appears in late adolescence (see Figure 1).

  Although the rate of disease is higher among the youngest children, most meningococcal illness (62%) occurs in children 11 years or older.

The new conjugate vaccine MCV4 promises longer duration of immunity and, perhaps, greater clinical efficacy than the polysaccharide vaccine MPSV4. Questions remain about booster doses, vaccinating young children, and safety.

Gary L. Freed, MD, MPH

Articles

Then and Now: Varicella vaccine

A new day in preventing meningococcal disease: Sizing up the available vaccines