The LID is developing live attenuated vaccines against RSV, HPIV3, HMPV, HPIV1, and HPIV2 (listed in the order of decreasing importance). Our emphasis is on RSV, given its importance, although we have clinical studies open for each of these viruses. These vaccines are developed and produced from cloned cDNAs using reverse genetic systems of our making and employing defined attenuating mutations of our making. We develop candidates in pre-clinical studies and prepare vaccine seeds. Vaccine manufacture and clinical evaluation is performed under contact under our supervision. Vaccines are evaluated clinically beginning in adults (who are seropositive for these common viruses), and moving into successively more vulnerable populations, namely seropositive older children (typically 12-59 months of age), followed by seronegative younger children and infants (typically 6 -59 months of age, depending on the virus). For RSV and HPIV3, viruses may be evaluated further in virus-naive infants 1-3 months of age. Adult studies are open-label;pediatric studies are double-blind placebo-controlled with a 2:1 ratio of vaccine to placebo recipients. Since 2006, these activities have been supported in part by a CRADA with MedImmune. RSV vaccine: RSV has two antigenic subgroups, A and B, that have extensive cross-reactivity and cross-protection. We presently are focusing on RSV-A, the more important of the two. We also have developed a reverse genetics system for RSV-B, and once a suitable candidate is prepared for RSV-A, we may prepare a similar RSV-B candidate if deemed necessary. 

 Under the CRADA, Medimmune is conducting a Phase 1/2a immunogenicity study in young infants with a recombinant rRSV (MEDI-559) that was developed by LID and contains a set of five independent attenuating elements. In a previous phase 1 study by LID, an earlier version of this virus (that differs by 27 silent mutations and appears to be phenotypically indistinguishable) was well-tolerated and immunogenic in 1-2 month old infants. The purpose of the present study is to get further data on safety and immunogenicity. We are conducting a phase I clinical study (NCT01459198) of a live attenuated RSV bearing deletion of the M2-2 coding sequence (delM2-2). This virus exhibits up-regulated viral gene expression that may increase its immunogenicity. This virus was well-tolerated and highly restricted in adults and seropositive children, consistent with a highly-attenuated phenotype. It presently is being evaluated in seronegative children 6-24 months of age. 

 We previously developed a version of MEDI-559 that was modified to increase its genetic and phenotypic stability. This virus, called RSV cps2, has been approved for a phase I study in seronegative children 6-24 months of age to begin in 2013 (NCT01852266). 
 In an accompanying report, we describe development of another vaccine candidate called delNS2del1313. This virus contains the deletion of the nonstructural protein-2 (NS2) gene, which encodes a protein that antagonizes host responses to viral infection, notably the type I interferon (IFN) response. It also contains deletion of codon 1313 in the polymerase L protein (del1313). Deletions of genes and codons can be refractory to reversion or compensation, and thus can provide increased genetic and phenotypic stability. This virus was shown to be suitably attenuated in non-human primates. It is entering phase I studies in 2013, beginning in seropositive children 12-59 months of age, to be followed by seronegative children 6-24 months of age (NCT01893554). 

 Thus, we have three promising candidates in or entering phase I studies: delM2-2, RSV cps2, and RSV delNS2del1313. These viruses have different properties (such as the presence and magnitude of temperature-sensitivity) and different mechanisms of attenuation (involving effects on RNA synthesis, regulation of RNA synthesis, IFN antagonism, among others). Our goal is to identify a suitable candidate to bring forward into larger phase II studies. 

 HPIV3 vaccine: We completed a phase I study of two viruses that combined the host range restriction phenotype of BPIV3 with the F and HN neutralization and major protective antigens of HPIV3. In one chimera, rB/HPIV3, all of the genes were from BPIV3 except HN and F;in the other chimera, rHPIV3-Nb, only the N gene was from BPIV3. Both viruses were well-tolerated in seronegative children, but the rB/HPIV3 vaccine was more attenuated and yet more immunogenic than rHPIV3-Nb, and thus may be preferred for further clinical development. The rB/HPIV3 virus also is being used as a vector to express RSV-F (see below). We also are evaluating an attenuated version of HPIV3 called rHPIV3cp45. This is a recombinant version of a biologically derived cold-passaged (cp) virus that previously had been shown by LID and collaborators to exhibit satisfactory infectivity, safety, immunogenicity, and lack of transmissibility in seronegative infants and children. LID re-derived this virus from cDNA to provide a known pedigree for safety reasons. This virus is being evaluated in a phase I clinical study in seronegative children 6-36 months of age in which two doses are given at a 6-month interval to investigate the durability of immunity and the feasibility of boosting at this interval (NCT01021397). Part of this study was done as companion protocols through Seattle Children's Hospital and the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Group. The results showed that the second dose induced an immune response in the few individuals who did not have a response to the first dose, and it boosted immunity in those who had a suboptimal response to the first dose. Importantly, this study also provided further evidence that this vaccine is safe and immunogenic. It is suitable to advance to larger studies. 

 HPIV1 vaccine: We previously used reverse genetics to generate a live attenuated HPIV1 vaccine candidate called rHPIV1-C(R84G/del170)HN(T553A)L(Y942A) that is attenuated by defined mutations including ones that have been engineered for genetic stability. Evaluation in adults and seropositive children 15 to 59 months of age showed that it is highly attenuated. We presently are completing a phase I study in seronegative children 6 to 59 months of age (NCT00641017). The available results suggest that the virus is over-attenuated. This may be corrected by removing one attenuating mutation.

 HPIV2 vaccine: We previously used reverse genetics to generate a live attenuated HPIV2 vaccine virus called rHPIV2-V94(15C)/948L/1724 that included stabilized mutations. This virus was highly attenuated in adults. Presently, it is being evaluated in a phase I study in seropositive children 15 to 59 months of age (NCT01139437). 

 HMPV vaccine: Last year, we initiated a phase I study of a live attenuated HMPV vaccine virus (rHMPV-Pa) in which the HMPV P gene was replaced by that of avian MPV, thus conferring a host range attenuation phenotype. Evaluation in adults and seropositive children 15 to 59 months of age showed that it is highly attenuated. The vaccine is presently being evaluated in seronegative children 6-59 months of age (NCT01255410). Vectored RSV vaccines: We are developing attenuated versions of HPIV1, 2, and 3 as vectors to express the RSV fusion F glycoprotein and RSV G glycoprotein, as described in an attached report. Appropriate candidates will be advanced to clinical studies, which may begin in 2014

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