Analysis of respiratory syncytial virus preclinical and clinical variants resistant to neutralization by monoclonal antibodies palivizumab and/or motavizumab.

BACKGROUND: Palivizumab is a US Food and Drug Administration-approved monoclonal antibody for the prevention of respiratory syncytial virus (RSV) lower respiratory disease in high-risk infants. Motavizumab, derived from palivizumab with enhanced antiviral activity, has recently been tested in humans. Although palivizumab escape mutants have been generated in the laboratory, the development of resistant RSV in patients receiving palivizumab has not been reported previously. METHODS: We generated palivizumab and motavizumab escape mutants in vitro and examined the development of resistant mutants in RSV-breakthrough patients receiving immunoprophylaxis. The effect of these mutations on neutralization by palivizumab and motavizumab and in vitro fitness was studied. RESULTS: Antibody-resistant RSV variants selected in vitro had mutations at position 272 of the fusion protein, from lysine to asparagine, methionine, threonine, glutamine, or glutamate. Variants containing mutations at positions 272 and 275 were detected in breakthrough patients. All these variants were resistant to palivizumab, but only the glutamate variant at position 272 demonstrated resistance to motavizumab. Mixtures of wild-type and variant RSV soon lost the resistant phenotype in the absence of selection. CONCLUSIONS: Resistant RSV variants were detected in a small subset (∼ 5%) of RSV breakthrough cases. The fitness of these variants was impaired, compared to wild-type RSV.

Genetic sequence analysis of influenza viruses and illness severity in ill children previously vaccinated with live attenuated or inactivated influenza vaccine.

In a large comparative study in 2004-2005, children aged 6-59 months vaccinated with live attenuated influenza vaccine (LAIV) experienced 55% fewer cases of culture-confirmed influenza illness compared with trivalent inactivated influenza vaccine (TIV) recipients. To better understand the characteristics of the breakthrough influenza illnesses, we analyzed the HA1 genetic sequence for all available samples and examined disease severity by strain and treatment group. All 48 A/H1N1 viruses were well-matched to the vaccine, whereas all 276 A/H3N2 viruses and 349 (96%) influenza B viruses were mismatched to the vaccine. The incidence of fever or lower respiratory illness did not differ by strain; however, LAIV recipients had less febrile disease and fewer lower respiratory illnesses than TIV recipients. Viruses of each influenza B lineage caused more illnesses than A/H1N1 viruses; strategies to enhance protection against multiple influenza B lineages should be pursued.