RSV Recombinant technology can be used to create live-attenuated respiratory syncytial virus (RSV) vaccines containing combinations of known attenuating mutations. Two live-attenuated, recombinantly-derived RSV vaccine candidates, rA2cp248/404?SH and rA2cp248/404/1030?SH, were evaluated in 31 adults and 95 children >6 months. rA2cp248/404/1030?SH was subsequently evaluated in 44 1-to 2-month-old infants. These vaccine candidates share 4 attenuating genetic elements and differ only in a missense mutation (1030) in the polymerase gene. Both vaccines were highly attenuated in adults and RSV-seropositive children and were well-tolerated and immunogenic in RSV-seronegative children. When compared with rA2cp248/404?SH, replication of rA2cp248/404/1030?SH was restricted in seronegative children (mean peak titer, 4.3 log10 vs. 2.5 log10 pfu/mL), indicating that the 1030 mutation had a potent attenuating effect. Although rA2cp248/404/1030?SH was well-tolerated in infants, only 44% of infants who received two 5.3 log10 pfu doses of vaccine had detectable antibody responses. However, replication of the second dose was highly restricted, indicating that protective immunity was induced. At least 4 of 5 attenuating genetic elements were retained in recovered vaccine viruses. rA2cp248/404/1030?SH is the first RSV vaccine candidate to be sufficiently attenuated for young infants. Additional studies are needed to determine whether rA2cp248/404/1030?SH can induce protective immunity against wild-type RSV. PIV3 A combination RSV and PIV3 live attenuated intranasal vaccine was evaluated for safety, viral replication 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 5 log10 plaque forming units (pfu) of each vaccine 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 virus was found after combined administration with 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 vs. 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. Both vaccines were immunogenic and antibody responses were not significantly different in the monovalent groups vs. the combination group. Combined 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 >38?C 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 3 field trial. DEN The live attenuated DEN-4 vaccine candidate virus rDEN4del30 was previously found to be safe and immunogenic at a dose of 5 log10 PFU. In a follow-up placebo-controlled Phase II clinical trial, rDEN4del30 was administered to three separate dose cohorts (3 log10 PFU, 2 log10 PFU, or 10 PFU) for further evaluation. Each dose cohort consisted of twenty vaccinees and four placebo recipients. Volunteers were monitored closely for adverse events and serum was collected on study days 28 and 42 for determination of neutralizing antibody titer. The vaccine was well tolerated by the vaccinees at all doses studied. The most common adverse events observed were a transient asymptomatic rash in more than 50% of vaccinees and a mild neutropenia in approximately 20% of vaccinees. No vaccinee developed a dengue-like illness. The vaccine was highly infectious and immunogenic with 95 ? 100% of vaccinees in each dose cohort developing a >= 4-fold rise in serum neutralizing antibody titer against dengue virus type 4. The rDEN4del30 vaccine is safe and induced an antibody response that was broadly neutralizing against genotypically diverse DEN-4 viruses. It is a promising vaccine candidate for inclusion in a tetravalent dengue vaccine formulation.
