The dose (quantity) of vaccine for the children and the adults is same for most of the vaccines, e.g., Tet-Vac, Meningococcal vaccine, MMR vaccine, Rabies vaccine, etc. For some vaccines the dose is different for the children and the adults, e.g., Hepatitis A, Hepatitis B, and TA vaccines.

for Varicella vaccine, in children one dose is recommended, but for individuals 13 years of age and above, two doses at 6 to 10 weeks interval are recommended. Why two doses of varicella vaccine are recommended at an interval and not the double dose at a time as in case of other vaccines?

Priya Marwah,
Senior Resident,
Department of Pediatrics,
S.D.M. Hospital,
Jaipur 302 015, India.

In general, nonreplicating vaccines may be considered as those with some adverse reactions (e.g., whole cell pertussis, whole cell typhoid) and those that are nonreactogenic (e.g., tetanus toxoid, carbohydrate antigens of S. typhi and meningoccoci, hepatitis A, hepatitis B, cell culture rabies vaccine). The dose is reduced in young children for reactogenic vaccines (e.g., S. typhi), but there is no technical reason to reduce the dose of nonreactogenic vaccines. However, since the cost of production of some vaccines are high, the dose reduction is for economic considerations for some vaccines (e.g., hepatitis A and B), so that the pediatric vaccine could be sold for a lower price. The doses of protein antigens required for immune stimulation is in general lower in children than in adults. In the case of rabies vaccine, the dose is not reduced in children since we want the best antibody response. In the case of exclusive pediatric vaccines (e.g., pertussis, Hib), the question does not arise, because the vaccines are formulated only for children. In the case of diphtheria toxoid, the dose is reduced in adults to prevant hypersensitivity (Arthus reaction) in those who are already immune.

In the case of replicating antigens, such as live virus vaccines, the dose given is for establishing infection (which is small), but the ultimate antigenic mass is what results from multiplication in the body (which is huge). For this reason Measles, Mumps, Rubella and Varicella vaccines contain only about 1000 to 5000 ‘median cell culture infectious’ doses. For the sake of simplicity, we can consider this as approximately equal to the number of virus particles. The exception is Oral Polio Vaccine, which, being poorly infectious, must be given as 500,000 to one million particles, and even then in tropical and subtropical developing countries only a minority of recipients get infected with types 1 and 3 viruses. Since the vaccine is meant to establish infection, there is no reason to alter the dose according to body mass. For live viruses, if you want to increase the dose to increase infectivity, doubling the number of particles does not usually achieve it and increasing by one log base 10 (that is, ten times higher) may be necessary.

When we found that the infection rate of OPV was so low in India, we solved the problem by documenting that 5 inoculations (doses) achieve some 90% infection rate and 7 doses achieve some 95% plus infection rate. In the USA and Europe, even 3 doses of OPV cause virtually 99% plus infection rates. These facts are reiterated here because it has relevance to the rules about Varicella vaccine, as shown below.

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. We do not have local data on response rates and I understand that some studies are in progress. However, until local data are generated, we must follow the available data and recommendations. Now you see, the number of doses are altered according to the response rate, and this rule should have also been applied to OPV. The Varicella vaccine recommendations are evidence-based, but the OPV recommendations were not. One extra dose of Varicella vaccine costs as much as the cost of over 300 doses of OPV.

The final point is about doubling the dose (potency) at one inoculation, rather than giving two single doses at one to two months interval. Superficially it would seem reasonable, but in reality it is not, as already alluded to. Faced with the problem of low infection rates in children given the standard dose of OPV, we gave children ten times higher dose (potency) as monovalent and triavalent OPV. The response rates of ten times dose was much less than the cumulative response rate of 5 sequential doses. With the ten times dose vaccine we would still have to give at least three times (amounting to 30 standard doses), for adequate response. On the other hand, we could manage to get similar result with 5 plus 2 (that is a total of 7) doses. We had found that there was a ‘hit or miss’ response with each dose in the previously uninfected child. So the response rate is approximately the same each time it is given, except that those who responded previously do not count any more in the calculation. A similar principle might be applicable with Varicella vaccine also. If we tried to increase the potency of the single dose for those above 12 years of age, perhaps ten times higher potency should be tried for a reasonable chance of near 99% response. Increasing from the standard 1500 particles to 3000 particles (that is, doubling the potency) would hardly matter as far as infection rate is concerned. As the Varicella vaccine is very expensive to manufacture, a ten times dose for single inoculation is not a practical solution, but a repeat dose is simple enough and cost-effective enough. Two doses double the cost, but a ten times dose will cost ten times more.

For nonreplicating protein antigens (e.g., hepatitis B), doubling the antigen content will markedly enhance the response rate or the antibody level achieved. This is because the antibody response is proportonal to the antigenic mass presented. For live virus vaccines, doubling the potency would hardly make a difference, because what matters is infection. ‘Hit’ with one dose is what we want. In those who had ‘miss’ with one dose of Varicella vaccine (say, some 15%), a second dose will ‘hit’ at the rate of some 80% pluse. Thus, my interpretation is that the principle of ‘hit or miss’ may be applicable to Varicella vaccine also. In other words, the improvement is unlikely to be due to a booster type effect, so common when nonreplicating antigens are given a second time.

T. Jacob John,
Emeritus Medical Scientist (ICMR),
439, Civil Supplies Godown Lane,
Kamalakshipuram,
Vellore 632 002, Tamil Nadu,
India