titers prior to vaccination, influences the degree of antibody response to vaccination (Table 14). Studies have shown that a second dose of vaccine induces the same kind of enhanced antibody response as that seen after primary vacci nation of individuals who have been previously sensitized by natural infection (105). Thus, two suitably spaced doses used for primary immunization would more uniformly induce higher initial antibody titers than a single dose in previously unsensitized individuals; subsequent doses would act as antibody boosters for that specific antigen.

Emulsification reduces the tendency toward febrile reactions, in part because of the smaller amounts of antigen required with the adjuvant, and in part because of the slower release of antigen. As was already noted, febrile reactions

were not observed with aqueous vaccines which contained less than 100 to 200 CCA units of virus (Table 11).

The only undesirable side effect of mineral oil adjuvants which was observed was the occasional occurrence of a nodule or cyst at the inoculation site. Some of these reactions were due to free oleic acid in certain batches of the emulsifying agent, Arlacel A (mannide monooleate). After this was corrected, such local reactions occurred less frequently and were believed to be due to inadvertent subcutaneous rather than intramuscular deposition of the inoculum, or to insufficient purification of the antigen (45, 106, 107). The occurrence of infrequent local reactions in those inoculated in large-scale programs in Britain (108) has discouraged the use of such vaccines, except in persons with a high risk of death

from influenza. Davenport (106) expressed the view that these reactions are

unimportant in comparison to the tens of thousands of excess deaths that generally accompany each visitation of epidemic influenza." Nevertheless. it would be advantageous to eliminate them by further investigation into their causes. Hilleman has reviewed the results of his studies on influenza vaccines emulsified in peanut oil (109, 110). It is likely that the use of split-virus preparations, viral subunits, or the use of different adjuvant substances will eliminate the few local reactions that have been associated with the use of emulsified vaccines.

The question has been raised concerning a possible delayed tumorigenic effect of emulsified vaccines. Beebe et al. (111) conducted a 10-year follow-up (since then updated to 18 years) (112) of the records of 18,000 men given mineral oil adjuvant influenza vaccine, of 4,000 given aqueous vaccine, and of 22,000 given formalinized saline placebo control in 1951-53. The vaccine groups have been compared with respect to all diag noses listed on the death certificates, autopsy protocols, and terminal hospital records. The findings are essentially neg ative with respect to malignant neoplasms, allergic diseases, and collagen diseases" (112. p. 337). Sufficient time has elapsed for a 23- to 25-year followup.

Tests have been subsequently conducted in mice to measure the safety of mineral oil adjuvant and its components

(113). Sporadic tumors that were not considered significant were observed in low incidence at the injection site in BALB/c and C57B1 mice of both sexes, and in female Swiss mice. A significant incidence of tumor formation was observed at the injection site in male Swiss mice.

Hilleman et al. (109) have questioned the meaning of these findings and their relevance to man in view of the controlled observations made in their laboratory, and in view of the findings of Beebe et al. (112). Hilleman et al. state that in their opinion, "the minor theoretical risk raised by the tests in these particular male Swiss mice seems small when compared to our need for an effective influenza vaccine." (109, p. 482).

Davenport has reviewed the results of continuing studies on vaccines emulsified in mineral oil (106). In summarizing 17 years of experience with the mineral oil adjuvant, Davenport proposed (106, p. 292):

..that the wealth of animal, chemical and clinical data available now urges adoption of the mineral oil adjuvant influenza virus vaccine for widespread use in the United States. That decision takes into consideration the probability that a new pandemic strain is expected to emerge shortly, and that the use of mineral oil adjuvant vaccines affords the greatest promise for coping with such a potential disaster.

Conclusion

The basic requirements for effective immunization include stimulation with a sufficient quantity of a suitably specific antigen to induce an immune response that is appropriate to protect against the pathological consequences of infection. An understanding of these requirements and the use of quantitative immunologic methods have shown that the nature of the problem of immunization against poliomyelitis, and the extent to which it remains unsolved, is entirely different from that of immunization against influenza For influenza, a killed virus vaccine exists which is in need of improvement. For poliomyelitis, there are two vaccines: one made of killed viruses and the other made of attenuated live virus

es.

Contrary to previously held beliefs about poliovirus vaccines, evidence now exists that (i) the live virus vaccine cannot be administered without risk of inducing paralysis, (ii) the killed virus vaccine does suppress virus spread and can eradicate poliovirus from a population. (i) booster doses of killed poliovirus vaccine are no more necessary than

booster doses of live poliovirus vaccine, and (iv) an orally administered live poliovirus vaccine is not necessarily more effective or more acceptable for poliomyelitis immunization than a killed poliovirus vaccine administered by injection.

A killed poliovirus vaccine is safe and effective under all circumstances when properly prepared (58, 114). The live poliovirus vaccine carries a small, inherent risk of inducing paralytic poliomyelitis in vaccinated individuals or their contacts. Where paralytic poliomyelitis is prevalent, this risk is relatively less than that of the natural disease; but where naturally occurring poliomyelitis has been suppressed or eradicated, the risk from live poliovirus vaccine is greater than that from the natural disease. This is similar to the present situation with smallpox vaccine.

nomical production of large quantities of a monovalent influenza virus vaccine, because of the relatively small amounts of antigen needed. Use of an adjuvant would also permit the preparation of a polyvalent influenza vaccine which would allow routine immunization programs to be developed.

Only by raising and maintaining the immunity index of the population against all antigenic variants that are pathogenic in humans will we be able to control influenza effectively. We will gain further understanding of the requirements for controlling influenza only by continued basic research and by epidemiological studies in the course of attempting to prevent outbreaks. As Kilbourne has said, "one approaches the prospect of 'eradication in biology with temerity, but it is not an impossible goal" (6, p. 538). With what is now known about the immune response, the influenza viruses, and immunologic adjuvants, we may well be able to do so.

The live poliovirus vaccine has been the predominant cause of domestically arising cases of paralytic poliomyelitis in the United States since 1972. To avoid the occurrence of such cases, it would be necessary to discontinue the routine use of live poliovirus vaccine. Since polio- Summary myelitis is still prevalent in many parts of the world, however, discontinuation of programs of routine vaccination would be unwise at this time. A killed poliovirus vaccine is available (115) both to maintain population immunity in areas of low poliovirus prevalence, such as the United States, and to eradicate poliovirus from areas of the world where poliomyelitis continues to be prevalent. The live virus vaccine should be used in the event of outbreaks of poliomyelitis in areas where unprotected individuals are at high risk.

A single vaccine against all known strains of influenza virus cannot be achieved with an aqueous preparation of killed viruses which can contain only a few strains because of the large quantity of each which is needed to stimulate immunity. It might possibly be achieved by a suitable combination of killed viruses or their purified antigens which is potentiated by an immunologic adjuvant. Water-in-oil emulsified vaccines more effectively evoke and maintain higher antibody titers than either aqueous vaccines or infection (95). More strains can be included in an adjuvant vaccine because smaller quantities of each antigen are required. Further enhancement is possible by choosing the most potent antigenic strains available to induce the broadest degree of antigenic crossreactions.

If a new pandemic strain appears, the use of a potent immunologic adjuvant would permit more rapid and more eco

The requirements for inducing immunity against an infectious disease are outlined, and the application of these requirements to the development of effective vaccines (vaccinology) is discussed. Influenza and poliomyelitis are examined from this viewpoint. and data are presented that demonstrate the effectiveness of killed virus vaccines against these diseases. A comparison between live and killed poliovirus vaccines suggests the desirability of returning to the use of a killed virus vaccine for the eradication of polio. The natural history of influenza and experience with vaccination suggest that influenza might be brought under effective control by routine immunization in childhood with a polyvalent killed virus vaccine potentiated by an immunologic adjuvant.

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