The Respiratory Viruses Section entered into a CRADA with MedImmune in 2006 to develop live attenuated virus vaccines for respiratory syncytial virus (RSV) subgroups A and B, human parainfluenza viruses types 1, 2, and 3 (HPIV1-3), and human metapneumovirus (HMPV). None of the ongoing studies have been completed, so there are no results to report. The following is a summary of the testing to date. HPIV1 vaccine: Human parainfluenza virus type 1 (HPIV1) is responsible for approximately 6% of pediatric hospitalizations due to respiratory tract disease with significant illness occurring predominantly in infants and young children, and therefore a vaccine is needed. The rHPIV1-C(R84G/del170)HN(T553A)L(Y942A) live attenuated virus vaccine was generated for intranasal immunization. The C(del170) mutation conferred a significant level of attenuation in hamsters and African green monkeys (AGMs) that closely resembled that of the CF170S mutation and will be of particular utility for vaccine development because it involves a deletion of six nucleotides rendering it highly refractory to reversion. The combination of the CR84G/HNT553A mutation set and the C170 deletion mutation yielded a virus designated rCR84G/170HNT553A that exhibited a satisfactory level of attenuation in hamsters and AGMs and was immunogenic and highly protective against HPIV1 wt challenge. A derivative of the rHPIV1-C(R84G/del170)HN(T553A) has been developed by the addition of a genetically stabilized ts att mutation in L to this recombinant. The L(Y942A) mutation is a substitution at amino acid position 942 of L that was engineered for increased genetic and phenotypic stability by the strategy of identifying a codon whose amino acid assignment yielded a ts att phenotype and which would require three nucleotide substitutions to revert to a codon that specifies a wt phenotype. The rHPIV1-C(R84G/del170)HN(T553A)L(Y942A) live attenuated virus vaccine candidate has been given to 35 seropositive adult volunteers. Only 4 were infected and vaccine virus was shed in minimal amounts. The virus is safe to proceed to the next group of seropositive younger subjects. HPIV2 vaccine: A live attenuated intranasal HPIV2 vaccine was generated using reverse genetic technology in a manner analogous to that for HPIV1 described above and was found to be immunogenic and protective in African green monkeys. The rHPIV2-V94(15C)/948L/1724 vaccine candidate has been given to 15 seropositive adult volunteers. Only 4 were infected and vaccine virus was shed in minimal amounts. The virus is safe to proceed to the next group of seropositive younger subjects. HPIV3 vaccine: There are two HPIV3 vaccine studies that are ongoing. First, clinical studies have been initiated with the bovine-human chimeric recombinant PIV that contains the HPIV3 HN and F protective antigens as replacements for the corresponding genes on a bovine PIV3 backbone (BPIV3). The rB/HPIV3 contains multiple attenuating BPIV3 genes. These studies are not complete so the results cannot be reported. Studies have been completed in seropositive adults (# =15) and seropositive older children (# = 10). Minimal shedding was seen in both populations and the virus was found safe to proceed to seronegative older children. These studies have been initiated, but recruitment is slow. The second candidate is HPIV3cp45. The biologically derived HPIV3cp45 vaccine candidate was found to exhibit satisfactory infectivity, safety, immunogenicity, and lack of transmissibility. Therefore, LID focused on deriving a HPIV3cp45 seed virus from cDNA that could be transferred to an industrial partner for eventual manufacture once efficacy was established. We established a reverse genetics system in which appropriate DNAs were electroporated into qualified Vero cells yielding rHPIV3cp45 virus with a known pedigree. A vaccine lot was manufactured using this seed material. In 2006, Medimmune entered into a CRADA with LID, and the LID HPIV3cp45 vaccine lot is currently being evaluated by LID and by Medimmune under this CRADA. LID has found that the cDNA-derived HPIV3cp45 vaccine replicates to over 7log10 TCID50/ml in Vero cells. A two dose vaccine regimen was tested in 10 6-12 month old seronegative infants and was found to be highly infectious, safe, and immunogenic (9 of 10 with antibody response) in the subjects. Thus, rHPIV3cp45 is highly infectious and immunogenic at 5log10 in seronegative older infants indicating the economic feasibility of this vaccine candidate. Only one of ten rHPIV3cp45 vaccinees was infected with the second dose given 1-2 months later indicating that a high level of resistance to re-infection was induced by this vaccine. A two dose study with rHPIV3cp45 in 2 month old subjects at 100,000 pfu is planned, and a two dose study is seronegative subjects older than six months is planned with the second dose given 6 months after the first dose. Two Phase 2b proof of principle efficacy studies with a RSV subgroup A vaccine candidate and with rHPIV3cp45, have been initiated. RSV vaccine: Medimmune has initiated studies under the CRADA leading up to a Phase IIb proof of principle efficacy trial with a recombinant rRSV containing a set of at least five independent mutations that contribute to attenuation. LID is also manufacturing two clinical lots of RSV subgroup A virus containing a deletion in M2-2 or NS1 gene. HMPV vaccine: LID is manufacturing two clinical lots of HMPV vaccine live attenuated virus vaccines.
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