Rubella: Reinfection in Vaccines and Natural Immunes Exposed in an Epidemic

PEARAY L. OGRA (State University of New York, Buffalo, N.Y.): We have some data which are very similar to what Dr. HORSTMANN has presented today. I think that the basis of herd immunity may really lie in the mechanisms of mucosal immunity, rather than in the circulatory antibody. Presently, we are studying comparative antibody responses in serum and secretions following natural or vaccine-induced rubella virus infection in a large group of children. Preliminary data suggest that although the antibody responses in serum are generally similar, following either type of infection, the responses in the secretions are strikingly different between the two groups. Those children who have been immunized with rubella vaccine usually fail to develop secretory antibody in their nasopharyngeal secretions. On the other hand, the natural disease almost invariably results in γA antibody production in the secretions. I was wondering if Dr. HORSTMANN had looked at the secretory immune responses among her patients. Dr. HORSTMANN : We are very much interested in this aspect of the problem, and are currently investigating it, particularly in relation to Dr. STANLEY PLOTKIN'S RA 27/3 vaccine. Unlike the HPV 77 derivatives and the Cendehill vaccine, RA 27/3 induces infection and serologic immunity when given intranasally. We do not know whether this vaccine will stimulate a greater secretory antibody response in the nasopharynx than the others, but it seems possible that it might do so. If so, it would have a distinct advantage, for as Dr. OGRA indicated, the superiority of natural over vaccine-induced immunity may be associated with local mucosal antibody and resistance. HARRY M. MEYER, Jr. (National Institutes of Health, Bethesda, Md.): Four years ago, our reports of rubella virus attenuation to this Society included data indicating that experimental animals immunized with either natural rubella or attenuated virus could undergo modified reinfection after challenge. The following year at these pediatric meetings, we showed that persons with antibodies as a result of earlier natural rubella or vaccination could also experience anamnestic increases in antibody. We noted that these reinfections were subclinical, highly abbreviated from a virologic point of view, and generally occurred in persons with relatively low antibody titers. Since 1967, several groups have confirmed and extended these findings. This past spring, we had the opportunity to reexamine this matter in considerable detail. Epidemic rubella entered the institution of our earlier studies involving 5 cottages. Each contained susceptible children, vaccinees, and others naturally immune. We examined and collected specimens from each person every day. In brief, 22 of 33 susceptibles were infected; all evidenced signs of rubella. Five of 22 vaccinees and 1 of 66 naturally immune children had subclinical reinfections as demonstrated by antibody increases. The virologic events were of particular interest: A. Virus recovery from pharyngeal swabs. With the daily swab collection, the primary rubella cases were shown to shed virus for an average of 17 days. The range was 9–29 days. The profuse pattern of virus excretion in primary rubella is apparent. In contrast, none of the 17 vaccinees resisting reinfection shed virus. Of the 5 vaccinees with an antibody boost only 2 had virus in their pharyngeal secretions. One of these had antibodies when exposed; this child shed virus in 4 specimens. The other was an apparent vaccine failure who never developed antibodies. When reinfected she had 8 virus-positive swabs. Each positive specimen was assayed for virus content and the quantitative differences were equally striking. The level of excretion in primary rubella ranged from 200 to 80,000 ID50/ml of swab with an average of 6,000. The vaccinee with antibodies had a peak of 50 ID50/ml of specimen. The vaccine failure was intermediate, excreting a maximum of 100 ID50. B. Virus recovery from heparinized blood. All persons with primary rubella were viremic. In fact, 83 % of blood samples collected in the 11 days preceding the appearance of antibodies yielded virus. Comparable specimens from the 5 reinfected vaccinees and the one naturally immune child reinfected were uniformly negative. Again, all positive specimens were assayed for virus content. The level of viremia in primary rubella averaged 800 ID50/ml with a range in individual cases of 10–10,000 ID50. None of these observations is particularly surprising since similar findings were made in studies of immunity resulting from live polio and rubeola virus vaccination. In terms of degree of resistance one expects attenuated viruses, in general, to evoke lower levels of antibody than their virulent counterparts. This is true of all the live vaccines—those for polio, smallpox, rubeola, mumps, yellow fever, and rubella. Lesser antigenic differences often exist between strains of the same virus. For example, attenuated rubella viruses are not identical and these variations can be correlated with relative resistance to reinfection. The important issue is to define what may be reasonably expected in the use of the available vaccines. Summing up the experience to date, we see no basis for altering the practical conclusions reached over a year ago: (1) Challenged vaccinees are protected, rarely shed virus, and are not demonstrably viremic; (2) in relation to herd immunity, vaccinated persons with antibody even if reinfected are not likely to participate in the spread of rubella virus in communities; and (3) concerning maternal-fetal infection, it is reasonable to expect significant fetal protection since vaccine-induced antibodies have been demonstrated to serve as a barrier to viremia. Dr. HORSTMANN : Some of Dr. MEYER'S data, as he pointed out, are similar to ours and to those of others. Our whole concern with the problem is that vaccination against rubella is unique, since it is not the vaccinee who is the main target, but the fetus, some 10 or 15 years hence. It may be that the present vaccination programs will prove effective, but as we gain more experience we tend to be more cautious in predicting an easy victory. The virus turns out to be an unusual agent, virologically and immunologically, and the infection has some strange epidemiologic features. Since there are so many uncertainties, what we need to do at this stage is to follow a number of vaccinated populations closely, and to be alert to the various possibilities that may be in store for us. I do not think that all of the answers are in by any means, nor will they be for some time to come.