Allen F. Woodhour

Vaccination and Revaccination with Polyvalent Pneumococcal Polysaccharide Vaccines in Adults and Infants

Summary Adult persons developed substantial antibody increases against essentially all pneumococcal capsular types following injection of polyvalent pneumococcal vaccine containing 50 μg of each capsular polysaccharide per dose. Revaccination 13 months after the previous immunization did not evoke important further increases in antibodies and there was substantially greater local reaction at the injection site than when the previous dose was given. This finding appeared due to local reaction of antigens with circulating antibodies in the area of injection, since there was a correlation between the measured amount of circulating pneumococcal antibodies and the degree of reaction. Infants less than 2 years of age who were given a half-dose of vaccine generally responded poorly when compared with adults. In studies of 3- to 5-month-old infants, there was some increase _in antibodies when a booster dose of vaccine was given 6 months after the first. Very high level antibody responses against all capsular types were obtained when revaccination was delayed until 2 years of age.

Studies in Human Subjects of Polyvalent Pneumococcal Vaccines

Summary Clinical studies of 12- and 14-valent pneumococcal capsular polysaccha-ride vaccines were carried out among 76 adults and 42 children. All but a small proportion of persons developed significant increases in homologous antibody against all capsular types in the vaccine. Clinical reactions consisted mostly of mild fever and self-limiting local reactions at the injection site, such as commonly seen following administration of killed vaccines. Antibody persisted remarkably well with only slight decline 20 months after the vaccine was given. The vaccine shows great promise for preventing disease and death caused by pneu-mococci and merits wide discretionary application. The authors are greatly indebted to L. Gorkum, M.D., E. McNicholas, M.D., and G. A. Starkweather, M.D., and to J. Campbell, R.N., K. W. Campbell, R.N., B.S., and J. Laughead, R.N., for professional medical and nursing assistance. V. Holmes, B.S., B. Last, G. Lowden, A.B., M.S., and J. Staub, B.S., provided important technical assistance.

Pneumococcal vaccine: dose, revaccination, and coadministration with influenza vaccine.

Summary Current pneumococcal vaccine contains 14 specific capsular polysaccharide antigens, each in 50-γg amount. Reduction of dosage to 25 or 12.5 γg per type gave reduced antibody responses in human subjects for most of the serotypes and these were less than current requirements of the U.S. Food and Drug Administration. Specific antibody following vaccination declines slowly and there was no worthwhile increase in antibody on revaccination 1 to 1.5 years following prior vaccination. Reduction in the dosage of antigen to one-half or one-fourth the 50 γg per antigen amount eliminated the enhanced local and systemic reactions noted previously when the full vaccine amount was given but the time interval between vaccination and revaccination was not long enough to test for the ability of the reduced dose to restimulate antibody production. Pneumococcal and influenza virus vaccines given at the same time into opposite arms showed no important reduction in antibody response to either vaccine and there was no increase in local or systemic reactions compared with that found when the vaccines were given alone.

Persistence of Pneumococcal Antibodies in Human Subjects following Vaccination

Abstract Adult persons who were given a pneumococcal polysaccharide vaccine containing 50 μg each of 12 serotypes showed an average 10-fold increase in amount of antibody to the 12 antigens (range 6- to 20-fold) 1 month after vaccination and there was an approximate average 50% decline in antibody 31/2 years later. Children who were 2 to 12 years old at the time of vaccination showed about the same antibody response to the vaccine but this was less persistent and there was about a 55% decline, on the average, after only 21 months, The findings are discussed in the light of need for revaccination and of the nature of antibody responses to polysaccharide antigens.

Hyperpotentiation by synthetic double-stranded RNA of antibody responses to influenza virus vaccine in adjuvant 65.

Summary Immunologic adjuvant 65 caused a strong enhancement of antibody response to influenza virus antigens in tests in animals. Complexed synthetic polynucleotides Poly I:C (rI:rC) and Poly A:U (rA:rU) produced comparatively weak potentiation of antibody response to these antigens and in certain instances, Poly A:U was inhibitory. Immunologic adjuvant 65 combined with the Poly I:C or Poly A:U acted synergistically to cause a hyperpotentiation of antibody response which greatly exceeded the additive effects of adjuvant and complexed polynucleotides tested singly. Such potentiation did not occur when the complexed polynucleotides were tested with alum adjuvant or when Poly I or Poly C was added alone. Poly I:C was generally more effective than Poly A:U. Maximal potentiation was demonstrated at 26 μg/ml of Poly I:C and there was no further enhancement when the concentration was raised to 260 μg/ml. Use of adjuvant 65 combined with complexed polynucleotides promises to contribute a new magnitude of immunizing capability to be obtained when used with influenza and other killed antigen preparations.

New Metabolizable Immunologic Adjuvant for Human Use. I. Development and Animal Immune Response.

Summary A new immunologic adjuvant, adjuvant 65, is described and the results of extensive tests of polyvalent influenza virus vaccine in the adjuvant are presented. The vaccine consists of a water-in-oil emulsion in which the adjuvant portion consists of peanut oil, mannide monooleate and aluminum monostearate. The adjuvant effect measured in terms of hemagglutination-inhibition antibody responses 28 days after vaccination in mice or guinea pigs is roughly equal to that obtained with Freunds incomplete mineral oil adjuvant. Adjuvant 65 influenza vaccine showed striking enhancement and long-term persistence of antibody in guinea pigs, rabbits and monkeys compared with the corresponding aqueous vaccines. The findings in histomorphologic-pathologic studies in animals and the clinical and serologic results obtained in large-scale studies in man are presented elsewhere. Adjuvant 65 shows promise of meeting the present urgent need for a safe and effective adjuvant for enhancing immunologic responses to viral and other vaccines and possibly also for treating allergic disease.

NEW METABOLIZABLE IMMUNOLOGIC ADJUVANT FOR HUMAN USE. 2. SHORT-TERM ANIMAL TOXICITY TESTS.

Summary A new immunologic adjuvant, called adjuvant 65, was assayed for toxicity, safety and irritancy in several species of animals. Clinical, gross and histomorphologic examinations were made. The reactions which resulted from adjuvant 65 vaccines were mild and inconsequential and far less than were obtained in comparable tests with Freunds incomplete mineral oil adjuvant vaccine. The comparative pathology for the 2 different kinds of adjuvant is presented and the theoretical and practical advantages of adjuvant 65 are discussed.

Ten-Year Follow-Up Study for Safety of Adjuvant 65 Influenza Vaccine in Man

Summary Clinical follow-up was made of more than 2000 persons who had received adjuvant 65 type influenza or aqueous type influenza vaccine or who had served as unvaccinated controls in studies in which vaccines were given up to 10 yr previously. No long-term effect was noted other than the occurrence in no more than 0.8% of persons observed of a persistent nodule that was difficult to palpate and that was no larger than a small pea. The rates for occurrence of nodules in vaccinated persons were not significantly greater than in the unvaccinated controls. There was no significant difference in the percentage of persons who died between the groups for respiratory disease, cardiovascular disease, cancer, or for miscellaneous cause (p > 0.15 for each category by Fishers exact test). All evidence points to safety of the adjuvant type vaccine both on short- and long-term observation. The authors are indebted to the personnel and physicians at the institutions where the studies were carried out; to A. Bitzer and J. Wilmer for nursing assistance; and to B. Abbott, G. Lowden, and B. Last for statistical compilations.

Clinical and Laboratory Investigations of Monovalent and Combined Meningococcal Polysaccharide Vaccines, Groups A and C

Summary Purified group A and C me-ningococcal polysaccharide vaccines prepared in these laboratories caused remarkably little local or systemic reaction and were highly effective in stimulating serum bactericidal antibody in studies carried out in adults. There was no measurable reduction in immunogenicity or increase in toxic reaction when the two vaccines were given in combined form in a single dose. Maximal antibody response was obtained following a single dose of vaccine and there was no increase in titer when additional doses were given 1 and 6 months later. Both vaccines retained their immunogenic potency on storage at 4° for at least 1 year and there was no reduction in immunogenicity on storage for up to 2 weeks at 4° following rehydration in thimerosal preservative solution. The authors are greatly indebted to Joan Goshow and Joan Staub for valuable technical assistance. We wish also to acknowledge the medical assistance of Drs. Frank D. Gray, George A. Starkweather, and W. Stuart Warren, and the nursing assistance of Janet Campbell, Karen Campbell, and Jane Laughead. The administrators and personnel of the Haverford Township Schools are cited for their helpful cooperation.

Polyvalent pneumococcal polysaccharide vaccines

A 14-valent pneumococcal vaccine has recently been licensed for general use after extensive testing in human subjects. Antibody production was satisfactory in 92% of individuals and a highly significant (76-92%) reduction was found in the rates for pneumococcal pneumonias caused by the capsular types present in the vaccine. Children over 2 years of age respond well to the vaccine, but younger children may not respond satisfactorily to some capsular types. In adults, the duration of the protective effect is at present unknown, but no substantial booster response was seen after a second dose at 1 year. Such a booster dose, in fact, induced a marked increase in the degree of local reaction at the injection site.