Studies in our laboratories during the past several years have been directed toward finding a highly active interferon inducer which would be worthy of clinical evaluation. It was found in these studies that capacity for inducing interferon by ribonucleic acids depends on (a) multistrandedness of RNA and (b) in certain instances, freedom from inhibitory proteins.The present paper reports the discovery that certain multistranded polynucleotide complexes are highly active in microgram amounts in inducing interferon and host resistance in vivo arid in vitro. Other reports inl the present series describe the isolation and demonstration of similar activity of double-stranded RNA from Penicillium funiculosurn (HeJ-RNA) I and from reovirus type 3.2 Materials and Methods.-(1) l'olynucleotides were purchased from Mann. Research Laboratories, New York, New York; Miles Laboratories, Elkhart. Indiana; and Sigma Chemical Co., St. Louis, Missouri. The designated polymers were mixed in equimolar concentration in phosphate-buffered saline, pH 7.0 (0.006 M sodium phosphate, 0.15 M NaCl), and complex formation, as determined by hypochromic effect, developed within the first minutes after mixing.3' 4Homopolymer solutions were stored at -20'C. In this paper the nomenclature of Inman and Baldwin will be followed.5 Thus, I, C, A, U, X, G, and DHU will signify homopolymers of hypoxanthine (for which the ribonucleoside is inosine), cytosine, adenine, uracil, xanthine, guanine, and dihydrouracil. CU, IU, AC, GU, and AG will signify copolymers of C and U, I and U, A and C, G and U, and A and G. Octanucleotides of A and U are signified by SA and 8U. A dephosphorylated trinucleotide of I is indicated by 31. CpA, CpG, GpU, and CpC signify dephosphorylated dinucleotides of C and A, C arid G, G and U, and C and C. A colon between polynucleotides signifies that complex formation has occurred, as shown by hypochromic effect. A mixed solution of polymers showing no hypochromic effect is indicated by (+) between polynucleotides. (2) Assays for interferon induction in rabbits, for interferon characterization, viz., species-specificity, trypsin sensitivity, molecular weight, and isoelectric point, and for induction of host resistance in mice were described previously.1 Other pertinent methods are presented in the text.Results.-(1) Induction of interferon in rabbits by complexed polynucleotides: (a) Induction: Table 1 shows that I: C induced interferon in rabbits when as little as a 0.5-,ug dose was given intravenously per rabbit. A: U and I+CpC were less active and induced interferon less consistently in repeat tests. The following were found to be inactive at doses between 50 and 200 ,ug per rabbit:
The worldwide importance of human hepatitis B virus infection and the toll it takes in chronic liver disease, cirrhosis and hepatocarcinoma, make it imperative that a vaccine be developed for worldwide application. Human hepatitis B vaccines are presently prepared using hepatitis B surface antigen (HBsAg) that is purified from the plasma of human carriers of hepatitis B virus infection. The preparation of hepatitis B vaccine from a human source is restricted by the available supply of infected human plasma and by the need to apply stringent processes that purify the antigen and render it free of infectious hepatitis B virus and other possible living agents that might be present in the plasma. Joint efforts between our laboratories and those of Drs W. Rutter and B. Hall led to the preparation of vectors carrying the DNA sequence for HBsAg and antigen expression in the yeast Saccharomyces cerevisiae. Here we describe the development of hepatitis B vaccine of yeast cell origin. HBsAg of subtype adw was produced in recombinant yeast cell culture, and the purified antigen in alum formulation stimulated production of antibody in mice, grivet monkeys and chimpanzees. Vaccinated chimpanzees were totally protected when challenged intravenously with either homologous or heterologous subtype adr and ayw virus of human serum source. This is the first example of a vaccine produced from recombinant cells which is effective against a human viral infection.
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