A combination RSV and PIV3 live attenuated intranasal vaccine was evaluated for safety, viral shedding and immunogenicity in doubly seronegative children age 6-18 months. More than one half of children screened for serologic eligibility were seronegative to both RSV and PIV3. The mean subject age was 10 months. RSV cpts-248/404 vaccine and PIV3-cp45 vaccines were combined in a dose of 100,000 plaque forming units (pfu) per 0.5 ml dose and compared to monovalent vaccines or placebo. The viral shedding pattern of RSV was not different comparing the monovalent RSV cpts-248/404 vaccine to the combination vaccine. Modest reduction in the shedding of PIV3-cp45 vaccine was found in the combination RSV cpts-248/404 and PIV3-cp45 vaccine relative to the monovalent PIV3 vaccine; 16 of 21 (76%) of the group given combination vaccine shed PIV3-cp45 versus 11 of 12 (92%) in the monovalent PIV3 vaccine group. Signs and symptoms of mild respiratory disease were common in all groups as were intercurrent wild type infections with PIV3, RSV or enteroviruses. Bivalent RSV/PV3 vaccine is feasible to develop for simultaneous administration, and further studies in larger numbers of children are warranted. A Phase II evaluation of live attenuated parainfluenza type 3 cp45 vaccine (PIV3-cp45) was conducted in 380 children age 6-18 months; 226 (59%) were seronegative to PIV3. Of the 226, 114 received PIV3-cp45 vaccine and 112 received placebo. No significant difference in the occurrence of adverse events, including the frequency of runny nose, cough, or fever 38C during the 14 days after immunization was noted. No difference in the occurrence of acute otitis media or serous otitis media occurred among the groups. Paired sera were available on 109 of the vaccinated seronegative subjects and 110 of the seronegative placebo recipients; 84% of seronegative vaccinated subjects developed a four-fold or greater antibody rise. The geometric mean post vaccine antibody titer was 1:25 among the vaccine group compared with <1:4 in the placebo group. PIV3-cp45 vaccine was safe and immunogenic in seronegative children and should be evaluated for efficacy in a phase III field trial. Parainfluenza type 3 virus (PIV-3) infections cause lower respiratory tract illness in children throughout the world. A licensed PIV-3 vaccine is not yet available. A live attenuated cold-adapted (ca) and temperature-sensitive (ts) PIV-3 vaccine, designated cp-45, was evaluated sequentially in open-label studies in 20 adults and in placebo-controlled, double-blind studies in 24 PIV-3 seropositive children, 52 PIV-3 seronegative infants and children, and 49 one-to-two-month-old infants. A single dose of this intranasal vaccine was evaluated in adults (1,000,000 pfu), seropositive children, and 10,000 and 100,000 pfu were evaluated in seronegative children. In the infant study, two 10,000 pfu doses of vaccine were administered at one or three month intervals. Safety, infectivity, immunogenicity and phenotypic stability of the vaccine were evaluated in all cohorts. The cp-45 vaccine was well-tolerated in all age groups, and infected 94% of vaccinated seronegative children and 94% of vaccinated infants. Although immunization with the first dose of cp-45 diminished the replication of a second dose in all infants, those immunized after three months shed vaccine virus more frequently than those immunized after one month (62% versus 24%, respectively). Antibody responses to PIV-3 were readily detected in seronegative children using a variety of assays; however, the IgA response to the viral hemagglutinin-neuraminidase was the best measure of immunogenicity in young infants. Of 109 vaccine virus specimens recovered from nasal washes, 98 were ts and 11 were temperature sensitive intermediate (tsi) viruses, with pinpoint plaques visible at 40C. tsi viruses appeared transiently at the time of peak viral replication, represented a very small proportion of the total virus shed, and were not associated with changes in clinical status. The cp-45 vaccine is appropriately attenuated and immunogenic in infants as young as one month of age. Further development of this vaccine is warranted. The dose repsonse to our DEN4del30 vaccine candidate is continuing.
