A commonly faced problem by practicing pediatricians is reluctance on the part of parents to get their babies administered with two or three injectable vaccines (DPT, Hepatitis-B Hib vaccines) simultaneously. They often request a gap of two to three days between two injections. Since none of these vaccines is a live vaccine-can they be administered within a gap of a few days (less than four weeks) ?

Deepak Goel,
22-6187, Pathergatti,
 Hyderabad 500 002,
A.P., India.

Reply

As more vaccines become available, our immunization practices. will get more complicated. The classical EPI schedule has 5 contacts during infancy when 5 injections and 4 oral inoculations are due. Thus there is no need for more than one injection per visit. One of the EPI injections is for BCG and another for measles vaccine. Three injections are for DPT which is indeed a combined product of 3 vaccines, namely diphtheria and tetanus toxoids and whole cell killed pertussis organisms. Thus we are already reducing the need for multiple injections by using the combination of DPT. Now we have to accommodate 3 doses of hepatitis B (HB) vaccine and also 3 doses of Haemophilus influenza b (Hib) vaccine for those opting for it. Already combinations of DPT plus HB and DPT plus Hib vaccines have been licensed in some countries in order to reduce the number of injections. DPT plus HB and Rib vaccines will also be available in India in due course. One manufacturer allows the reconstitution of the Iyophilized Hib vaccine with the liquid DPT vaccine in order to reduce one injection.

However, for us in India at the present time these combination vaccines are not yet avail- able and we must see how we can reduce the need for multiple injections at one visit. When properly counselled, most parents do accept 2 injections at a time for the infant. Thus, BCG and HB vaccine may be given to the newborn, usually' without objections. Later when DPT is due at 6 weeks, one of the two, HB, or Hib vaccine, may also be given at the same visit. , Technically speaking, the second dose of HB vaccine should have preference over Hib at this time. In that case, at the next two visits for DPT, Hib vaccine could also be given. That still leaves a third dose of Hib which could be given at 18 weeks. Then, the third dose of HB vaccine could be given itself at about 6 months of age or. at the same .time' as the measles vaccine at 9 months plus.

But this solution is for those who accept 2 injections at a time. Dr. Goel's question is about the situation in which parents do not like even 2 injections at a time. Obviously, there will be some parents who will, given the option, prefer to have only one injection. In such cases, can different vaccines be given with short intervals between them? Based on our knowledge of immunological principles, I do not see any reason to expect interference between responses to different vaccines, in most cases. If there is no interference when given simultaneously, it is likely that the same case applies when given at a few days or a week or two of intervals. There is one exception and that is measles vaccine, which is known to induce slight perturbation of the Th1 pathway. This is a temporary and mostly in- consequential event, but we are evoking immunological principles here and we must take note of this phenomenon. Therefore, I feel that another vaccine is best avoided, if it can be, during the days and up to 4 weeks after the primary dose of measles or MMR vaccine, as the case may be. What might happen if a vaccine is given a week after measles vaccine? Since it is the Th1 pathway that is mainly affected any vaccine with predominantly cell mediated immunity response might have reduced level of response. BCG is the only such vaccine that we use today, but earlier, small- pox vaccine, was of the same category. In the case of other vaccines, probably there might be no reduction in response, but knowing that T helper cell (CD4) function is also important for robust humoral immunity, it is better to keep this principle as a rule of thumb. That is, give another vaccine either at the same time with measles vaccine or else give a gap of 4 weeks.

In summary, the answer to Dr. Goel's question is that in general, reasonable and practical intervals can be used between doses of different vaccines. However, I do not consider intervals of 2 to 3 days between doses as advisable, because that is when we expect the height of local and systemic reactions to a dose of injected vaccine. To inject another dose at that time is worse than giving the two together at the same time. Perhaps even one week is too short in my personal (purely subjective) opinion. Intervals of 10 days or 2 weeks would be more humane, I think.
 

T. Jacob John,
Chairman,
Committee on Immunization and
President, Indian Academy of Pediatrics,
 2/91 E2 Kamalakshipuram,
Vellore, Tamil Nadu 632 002,
India.
 

Intervals Between Different Vaccines

I seek a classification on the following two issues:

I. Can measles and BCG vaccines be given together to a child who has come unvaccinated at one year of age?
2. A minimum gap of one month is usually recommended between two vaccines. Is this concept applicable to the same

vaccine or also holds true for any two vaccines?
 

Ramesh K. Agarwal,
151, Street No.7,
 Barkat Nagar,
Jaipur 302 015, India.
 

Reply

Dr. Ramesh Agarwal has wisely chosen measles vaccine as of high priority for a previously unvaccinated child of one year. In most communities in India, diphtheria and pertussis have become so uncommon that there may not be an immediate threat of these diseases. So, immunization can wait a little bit, if postponement is necessary. The same can also be said of poliomyelitis at the present time. The risk of tetanus is usually at an older age. On the other hand tuberculosis is ram- pant almost everywhere, and there is justification in choosing BCG as another vaccine to be given as soon as possible. So the question whether measles and BCG vaccines could be given simultaneously is quite relevant.

Measles vaccine had been shown to inhibit the take of smallpox vaccine during yesteryears. This might have been due to increased levels of interferon, or due to some other mechanism. A very mild degree of suppression of CD4 cell response has been shown to occur following measles immunization. This is believed to be inhibitory to the development of cell mediated immunity. The desired immune response to BCG is cell mediated. Therefore, it is prudent to avoid giving BCG during about 4 weeks after giving measles immunization. Since the effect of measles vaccine takes about one to two weeks to develop, perhaps it might be all right to give BCG at the same time as the measles vaccine. Personally, I would not do it, but choose one or the other. If the season is known for high prevalence of measles, I would give measles vaccine first and give BCG 4 weeks later. Otherwise, I would give BCG first and give measles vaccine 4 weeks later. I must add that I have not come across any specific study in this regard and if any of our readers has any relevant information, please share it with me.

Another way to approach this issue is to ask which other vaccines could be given along with measles vaccine. Every other vaccine, live or non-infectious, predominantly stimulates antibody response. Therefore, in principle, any other vaccine could be given simultaneously with measles vaccine. On the other hand, perhaps it is a prudent choice not to give any vaccine during the 4 weeks after measles immunization. It should not be for- gotten that the previously unvaccinated child requires not only measles and BCG vaccines but also all other pending vaccines.

The second question about intervals between doses of vaccines has been addressed previously, more than once, in the columns of Indian Pediatrics. However, being an important practical issue, reiteration is a legitimate demand. When a vaccine is given in divided doses, such as DPT, Hepatitis-B vaccine, etc. a minimum interval of 4 weeks between doses is necessary to ensure adequate antibody response. Increasing the interval improves the height of antibody response. That is why the third dose of HB vaccine is recommended 4 months after the second. Even for this vaccine, 4 weeks between the second and third doses are sufficient for excellent seroconversion. The WHO accepts a schedule of 3 doses of HB vaccine at monthly intervals. On the other hand, when rapid anti- body response is desired, for example for Japanese encephalitis vaccine just before the epidemic season, or for whole cell killed typhoid vaccine, a shortened interval (2 weeks) between the first and second dose is acceptable. In the case of post exposure rabies immunization, very short intervals are necessary for early antibody response, namely 3 doses in quick succession, followed by one dose after one week and yet another after 2 weeks. The increased number of doses ensures reasonably high antibody levels for the purpose of long term survival of anti- bodies in body fluids.

As already indicated above, barring the exception of measles vaccine as already discussed, there is no immunological reason to keep a minimum 4 weeks intervals between doses of different vaccines. When vaccines are given by injection, which parent would like the child to be hurt frequently? There- fore, for reasons of empathy and for avoiding any cumulative reactions like pain, swelling or fever, it may be better to give clinic appointments for immunization at some reasonable intervals and 4 weeks is as good as any other. We must increasingly prefer combination vaccines when possible to reduce the number of injections. We must also seriously consider if an anaesthetic skin application might be a practical and acceptable proposition.

T. Jacob John,
Chairman,
Committee on Immunization and
President, Indian Academy of Pediatrics,
2/91 E2 Kamalakshipuram,
Vel/ore, Tamil Nadu 632 002,
India.