Is There a Correlate of Protection for Measles Vaccine?

(See the Review by Bolotin et al., on pages 1576–83.)

Measles is rampant again, sadly, in Europe and in the United States [1, 2]. For that reason it is important to know the correlates of protection against measles, to evaluate the susceptibility of both individuals and populations, including those who have previously received measles vaccine.

To define a correlate of protection by a vaccine is not easy, as I have learned over the years. In 2001, I first wrote about the subject, attempting to simplify it with certain definitions and criteria [3]. Subsequently I realized that nothing is simple, as has been noted from times immemorial [4]! The reasons for this lack of simplicity are manifold, including lack of standardization of critical immunologic tests, the multiplicity of antibody and cellular immune functions, and the many ways in which those functions interact. In addition, challenge dose and number of challenges also figure into estimations of correlates.

It is in face of these daunting circumstances that Bolotin et al, in the current issue of The Journal of Infectious Diseases [5], have reassessed the data for correlates of protection by measles vaccine. The field has long depended on the study of a measles epidemic by Chen et al [6], in which the subjects had given blood specimens before vaccination and after a subsequent outbreak of measles. The conclusion drawn from that study was that 120 mIU of measles virus antibody, based on results of an enzyme-linked immunosorbent assay (ELISA), correlated with protection against clinically diagnosed measles. Whereas that was, and is, a useful number, its accuracy has not been confirmed for several reasons.

First, the antibody level was measured by an ELISA, which does not measure antibodies with respect to their function. Antibodies have multiple functions, including neutralization, prevention of attachment to the organism, and enhancement of natural killer cell activity. In addition, cellular responses to measles virus are ill defined, and in some other diseases those responses are additive to protection by antibodies. Thus, it is important to look again at the correlates of protection for measles vaccine, which Bolotin et al have attempted to do.

In the 19th century, Panum [7] recognized that natural infection with measles virus in the Faroe Islands conferred permanent immunity against the disease, and, indeed, that observation may still be true. However, the vaccine gives an attenuated infection, and it is not the case that antibody levels remain permanently elevated in vaccinees. The current situation is responsible for reevaluation of the long-term efficacy of measles vaccine [8].

Although the great majority of measles vaccinees remain seropositive indefinitely, as in the case of mumps vaccine the circulation of new measles virus genotypes may be important. Genotypes B3 and D8 are now circulating, and these viruses are not as well neutralized by antibodies to the vaccine genotype (ie, genotype A) as by antibodies raised against the new strains [9]. Even more importantly, a minority of vaccinees lose antibodies with time and thus become susceptible to infection with wild measles virus. Cherry and Zahn have recently shown that 11% of measles cases in California occurred in vaccinees who received 2 vaccine doses [10]. A study done in Spain observed that, between 2003 and 2014, 132 measles cases were observed in 2-dose vaccine recipients [11]. In a psychiatric unit for adolescents, a case of measles in an unvaccinated individual resulted in a 7% rate of measles in vaccinated contacts, although the disease was mild [12]. An outbreak in Dutch medical staff suggested that low levels of neutralizing antibodies in vaccinees correlated with failure of protection [13]. Unfortunately, the fully protective level of neutralizing antibodies is not known.

The possibility that subclinical or paucisymptomatic infection with measles virus occurs in vaccinees must also be considered. Although I know of no evidence for virus excretion by vaccinees with some but not all symptoms of measles, virus isolation from such patients should be attempted. Moreover, the reasons for waning of antibodies in some vaccinees are not known, and the establishment of new correlates of protection based on neutralizing antibodies or other immune functions may be needed.

The measles epidemics occurring in Europe and the United States could serve a useful purpose if specimens were obtained from exposed contacts before they are or are not infected. The scientific community should take advantage of the current situation brought on by vaccine resistance and vaccine ignorance to better define the correlates of measles immunity.

References

Note

Potential conflicts of interest. S. A. P. reports personal fees from Merck, GlaxoSmithKline, and Sanofi outside of the submitted work. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.