A highly potent extended half-life antibody as a potential RSV vaccine surrogate for all infants

Abstract

Prevention of respiratory syncytial virus (RSV) illness in all infants is a major public health priority. However, no vaccine is currently available to protect this vulnerable population. Palivizumab, the only approved agent for RSV prophylaxis, is limited to high-risk infants, and the cost associated with the requirement for dosing throughout the RSV season makes its use impractical for all infants. We describe the development of a monoclonal antibody as potential RSV prophylaxis for all infants with a single intramuscular dose. MEDI8897*, a highly potent human antibody, was optimized from antibody D25, which targets the prefusion conformation of the RSV fusion (F) protein. Crystallographic analysis of Fab in complex with RSV F from subtypes A and B reveals that MEDI8897* binds a highly conserved epitope. MEDI8897* neutralizes a diverse panel of RSV A and B strains with >50-fold higher activity than palivizumab. At similar serum concentrations, prophylactic administration of MEDI8897* was ninefold more potent than palivizumab at reducing pulmonary viral loads by >3 logs in cotton rats infected with either RSV A or B subtypes. MEDI8897 was generated by the introduction of triple amino acid substitutions (YTE) into the Fc domain of MEDI8897*, which led to more than threefold increased half-life in cynomolgus monkeys compared to non-YTE antibody. Considering the pharmacokinetics of palivizumab in infants, which necessitates five monthly doses for protection during an RSV season, the high potency and extended half-life of MEDI8897 support its development as a cost-effective option to protect all infants from RSV disease with once-per-RSV-season dosing in the clinic.

Infants Infected with Respiratory Syncytial Virus Generate Potent Neutralizing Antibodies that Lack Somatic Hypermutation

“…These differences in the dominant epitopes targeted by infant and adult responses provide a unique opportunity for prevention strategies that seek to combine passive and active immunization. For example, vaccines could be designed to preferentially elicit site III antibodies, which would not compete for binding with second-generation prophylactic antibodies that target antigenic site Ø, such as MEDI8897 (Griffin et al, 2017; Zhu et al, 2017). In addition, antibodies elicited by a site-III-specific vaccine would not block access to the apex of the preF trimer on infectious virions, allowing the development of neutralizing antibodies directed against antigenic sites in this region to occur during RSV infection.…”

“…Antigenic site V, located between sites Ø and III, was recently identified and shown to be the target of additional preF-specific antibodies that are potently neutralizing (Gilman et al, 2016; Mousa et al, 2017). A preF-specific antibody that targets site Ø and contains Fc modifications to extend serum half-life (MEDI8897) is currently in late-phase clinical trials (Griffin et al, 2017; Zhu et al, 2017). …”

Promising approaches for the treatment and prevention of viral respiratory illnesses

“…MEDI8897 offers 9-fold greater potency than palivizumab and has extended half-life in primates, suggesting a once per season dosing. 128 Candidate vaccines are based on live attenuated strains, subunit, vector, and nanoparticle technologies with a range of adjuvants. Chimeric and combination vaccines using expression vectors in VLPs show much promise.…”

Respiratory syncytial virus

“…Another monoclonal antibody product, Suptavumab (Regeneron Pharmaceuticals, Tarrytown, NY) failed to meet the primary outcome of preventing medically attended RSV infection in preterm infants born at >29 weeks of gestation in a 2017 Phase III infant clinical trial (http://investor.regeneron.com/releaseDetail.cfm?releaseid1037184). A novel investigational monoclonal antibody, MEDI8897 (MedImmune and AztraZeneca LLC), is a recombinant human immunoglobulin G1 monoclonal antibody that targets the pre-fusion conformation of the RSV F-protein [52]. This monoclonal antibody binds a highly conserved epitope on RSV F and neutralizes a diverse group of RSV A and B strains with over 50-fold higher activity than Palivizumab.…”