Development of live attenuated pediatric RSV vaccines Laboratory of Infectious Diseases, NIAID, NIH (Ursula Buchholz, Peter Collins) Center for Immunization Research, JHU (Ruth Karron) Infant with RSV disease Division of Clinical Research, NIAID, NIH IMPAACT, NIAID and NICHD, NIH (Betsy McFarland, Coleen Cunningham) MedImmune
Why a live RSV vaccine? Needle-free, adjuvant-free; a single dose is substantially immunogenic Broad stimulation of innate, cellular, humoral immunity Direct stimulation of respiratory tract immmunity Attenuated RSV strains provide all of the viral antigens IN immunization avoids immune suppression by maternal antibodies Live vaccines induce broader, more effective immunity than subunits in virus-naïve recipients (e.g. influenza vaccines) Killed and subunit RSV vaccines prime for enhanced RSV disease in RSV-naïve recipients
Why a live RSV vaccine? Needle-free, adjuvant-free; a single dose is substantially immunogenic Broad stimulation of innate, cellular, humoral immunity Direct stimulation of respiratory tract immmunity Attenuated RSV strains provide all of the viral antigens IN immunization avoids immune suppression by maternal antibodies Live vaccines induce broader, more effective immunity than subunits in virus-naïve recipients (e.g. influenza vaccines) Killed and subunit RSV vaccines prime for enhanced RSV disease in RSV-naïve recipients Immunization of infants against RSV requires a live vaccine
Planned timing of a live RSV vaccine 1 or 2 doses beginning at 4 or 6 months Boost at 12-15 months 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 age (months) The present study examines a single, primary immunization, evaluated in RSV-seronegative infants 6-24 months of age
Phase I clinical studies of live RSV vaccines: Stepwise evaluation in increasingly vulnerable populations Adults (unscreened), n = ~10-15 RSV Seropositive Children 15-60 Months, n = ~15 (V:P = 2:1) Present population: * RSV Seronegative Children 6-24 Months, n = ~30 to 51 (V:P = 2:1) * Testing in naïve recipients is restricted to April-October
Three key study objectives: 1. Tolerability/reactogenicity: Frequency of vaccine-related solicited events Studies are conducted in the RSV off-season (April 1to mid-october) Findings can be obscured by background respiratory infections, even in the off-season 2. Magnitude of vaccine virus replication: Measure the amount of vaccine virus shed This gives a second, more quantifiable measure of attenuation In initial phase I studies, this necessitates extensive nasal wash sampling; subsequent studies have less sampling Virus recovery is complicated by the labile nature of RSV We historically use plaque titration, and are introducing qpcr to measure replication 3. Immune response to RSV: Quantify the serum antibody response ELISA antibody against RSV-F; RSV-neutralizing antibodies Historically, nasal wash antibodies have been difficult to quantify reliably and will not be measured Labwork is done at the Center of Immunization Research, JHU.
3 attenuated RSV vaccine candidates with different properties in clin. studies Mutations in red are temperature sensitive RSV cps2 (P1114) NS1 NS2 N P M SH G F M2 cp cp cp cp cp SH 248 404 1030 stabilized Multiple point mutations + 1 gene deletion = 5 independent attenuating loci Highly temperature sensitive, provides further restriction in LRT Tendency for some of the population to lose 1 attenuating locus L RSV NS2/ 1313/ I1314L NS1 NS2 N P M SH G F M2 NS2 Deletion of IFN antagonist may provide increased immunogenicity L 1313 I1314L (CIR-288) Deletion L residue 1313 confers a moderate ts phenotype Expect gene deletion to be highly stable RSV M2-2 NS1 NS2 N P M SH G F M2 L RSV LID M2-2: IMPAACT 2000 Deletion of RNA regulatory protein: Increased antigen expression may increase immunogenicity Expect gene deletion to be highly stable Not temperature sensitive We are evaluating two slightly different versions: RSV MEDI- M2-2 and RSV LID- M2-2
Lead live-attenuated RSV strains under clinical evaluation 2013 2014 2015/2016 RSV MEDI M2 2 CIR seroneg. 6 24 mo RSV cps2 P1114 seroneg. 6 24 mo RSV LID M2 2 IMPAACT 2000 seroneg. 6 24 mo Projected studies: 1. Expanded study with lead candidate identified from the 2013/2014 studies 2. Modified RSV candidate RSV NS2 1313 CIR seropos. 12 59 mo RSV NS2 1313 CIR seroneg. 6 24 mo 3. Bovine/human PIV3 vector expressing RSV F
Summary Immunization of infants requires a live RSV vaccine. Several candidates are being evaluated. This is because they may differ in (i) attenuation and tolerability, (ii) immunogenicity, and (iii) stability. This is assessed in small numbers of infants and children, which is challenging. RSV is a labile virus, and considerable care is needed in preparing vaccine and in processing nasal washes. We hope to have information on 3 different candidates by the end of 2014. This may identify a lead candidate that will be taken to a larger study in 2015/2016.
Summary Immunization of infants requires a live RSV vaccine. Several candidates are being evaluated. This is because they may differ in (i) attenuation and tolerability, (ii) immunogenicity, and (iii) stability. This is assessed in small numbers of infants and children, which is challenging. RSV is a labile virus, and considerable care is needed in preparing vaccine and in processing nasal washes. We hope to have information on 3 different candidates by the end of 2014. This may identify a lead candidate that will be taken to a larger study in 2015/2016. It also is possible that: We may identify a promising candidate but decide a different version (e.g., more attenuated) should be evaluated in 2015. A number of modified versions are being developed as back-ups. Some of the initial testing may be inconclusive and require further confirmatory evaluation (e.g., to evaluate tolerability) We also anticipate evaluating a B/HPIV3 vector expressing RSV-F in 2015.