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Images in Clinical Practice Indian Pediatrics 2001; 38: 427-429 |
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Dose of Varicella Vaccine |
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In response to a question by Dr. Marwah, why two doses of Varicella vaccine are recommended for individuals 13 years of age and above, Dr. Jacob John had stated "In Japan, USA and Europe, the infection rate (measured as seroconversion rate) of varicella vaccine is 97% or more, in healthy children from one year to 12 years. In those of 13 years of age and above, the observed seroconversion rates are only 78% to 82%, for reasons which are not clear. When a second dose was given, the cumulative response rate increased to 99%. This empirical (in other words, experimental) observation is the reason for the recommendation of two doses for those above 12 years of age"(1). Seroconversion does not necessarily mean seroprotection. Seroprotection is provided by the level of antibody production and GMT (Geometric Mean Titration) correlates with seroprotection. In one study(2) it was found that GMT of 10 and above provided protection against varicella infection. The GMT varied between 11.6 and 12.7 in children from 12 months to 12 years of age, but GMT was 6.0 for subjects 13-17 years of age, i.e., well below the protective level, although seroconversion rate was 79% in this age group. GMT rose to 13.3 after second dose of vaccine in 100% children. "GMT has inverse correlation with body mass index (BMI) and not with age. Because BMI increases with age, the effect of BMI should be taken into consideration when assessing the response to all vaccines by age. The explanation for association between BMI and response to vaccines has not been elicited fully but may be related to hormonal factors or as yet undefined difference in immune function..."(3). For varicella vaccine GMT to be above protective level, may be the BMI after 13 years age is critical, so for practical purposes 13 years age is kept as cut off point for two doses of vaccine. The varicella vaccine available in India previously had 2000 plaque forming units (PFUs) per dose. Recently, another manufacturer has introduced varicella vaccine which has 1000 PFUs per dose, but the recommendation is to administer a single dose even above 13 years of age. No explanation or reasons for this schedule is given, this point also needs clarification. Yash Paul,
Even though the specific purpose of the question is to clarify the reason for the recommendation of one dose of varicella vaccine up to 12 years of age and 2 dose from 13 years, the question contains some terms and concepts that must be clarified first. I shall define or describe them. Seroconversion: The change from antibody negative state to antibody positive state. Infection always induces seroconversion. When vaccination induces seroconversion, it has induced the expected immune response. Vaccination is the process of inoculating vaccine; immunization is the process of inducing immune response. These terms are usually used as synonyms for obvious reasons. Seroprotection: The state of protection (from disease), due to the presence of humoral immunity, or antibody detectable in plasma or serum. This term is usually used in the context of the level of such antibody necessary for protection. The seroprotective antibody level has been defined for viral hepatitis B and for invasive H. influenzae b disease. I do not recall reading about such seroprotective antibody level for varicella. Antibody titer: The reciprocal of the highest serum dilution at which antibody has been detected. There are methods to quantitate antibody protein content (or concentration) in serum (or plasma) either by weight (such as micrograms per ml) or as optical density in enzyme immune assays. The term titer may then be used rather loosely to refer to the level of antibody. Antibody titer should be defined in each study. Geometric mean titer (GMT): The mean antibody titer in a group of individuals (usually those who have seroconverted). Since serum dilutious are geometric (such as 1/10, 1/20, 1/40 and so on) the mean value cannot be calculated on arithetic calculation, but it must be on geometric calculation. Being the mean of a group, GMT cannot express the seroprotective level of antibody, which refers to the level in the individual. When a live vaccine induces seroconversion, protection from disease is usually assured. If the antibody level achieved is low, then immunity may wane and the individual may once again become susceptible to the disease. Disease occurring in spite of immunity is called "break-through" disease. As far as varicella vaccination is concerned, the results of the study of White et al. cited in the question, are very important, the seroconversion rates and GMTs of children given one dose of varicella vaccine were as follows: Age Seroconversion rates% GMT 12-15 mo 98 11.7 16-23 mo 97 12.7 2- 4 yr 97 11.6 5-12 yr 95 12.2 13-17 yr 79 6.0 In various age groups tested, persistence of antibody (one year later) was found in 99 to 100%. Thirty eight non-seroconverted children were given a second dose and all of them seroconverted. Many seroconverted children came in contact with varicella, and most were protected. Of those who developed "break-through" varicella, no antibody level at seroconversion could be attributed as protective or non protective. All cases of "break–through" disease were mild. Thus, the interpretation suggested in the question, the GMT of 6 (or less than 10) was non-protective, has no scientific basis. The authors themselves stated: "the presence of detectable antibody is, in general, associated with protection". When we read scientific papers, we must read them critically and with caution, lest we should misinterpret what is presented. The second study cited in the question, by Shaw et al. was not on varicella vaccination, but on hepatitis B vaccination. That study showed that the GMT of antibody response was significantly higher when the vaccine was injected in the arm than when injected in the buttock; this difference was not correlated to body mass index by the investigators. There is a fundamental difference between a live virus vaccine and a non-replicating protein antigen vaccine. The former vaccine contains live virus which must multiply in the body of the host before an immune response is mounted. If the live virus gets inactivated (by heat or ultraviolet light) it loses immunogenicity. The non-replicating antigen is given in an amount that has been pre-determined to be immunogenic. Therefore, comparisons of the factors determining antibody response (represented by GMT) must be done with caution. I have been unsuccessful in identifying the source of the quotation relating to body mass index. It is under-standable that the total quantity of antibody distributed within a small body may show higher concentration than when diluted within a larger body. The recommendation to give 2 doses of varicella vaccine to children above 12 years is not based on body mass index, but on the observed reduction in seroconversion rate from 13 years of age. The seroconversion rate is enhanced with a second dose. If a varicella vaccine is shown to have near 100% seroconversion rate even in children older than 12 , then it can be recommended as a single dose vaccine. During the recent Asian Congress of Pediatrics (Taipei, March 2000), I had an opportunity to ask Dr. Takahashi (who developed the Oka strain varicella virus vaccine) about the dose schedule followed in Japan. There, only one dose is given irrespective of the age of the vaccinated person and the seroconversion rates are very high across wide age spectrum. However, Dr. Takahashi also said that the varicella vaccine (Biken) used in Japan has a titre of over 10,000 plaque forming units. In summary, the onus of documenting near 100% seroconversion in teenagers given one dose of varicella vaccine rests with the company that claims that a single dose of their vaccine is sufficient beyond 12 years of age. Until such data are developed or divulged, we must use the standard recommendation of 2 doses beyond 12 years. I must add here that we urgently need Indian data in terms of seroconversion rates in children vaccinated with varicella vaccine. Since varicella itself occurs in a wider age spectrum than in Japan, Europe and North America, perhaps the vaccine response may be different in India, than elsewhere. A good topic for an MD thesis. T. Jacob John, |
