Development of live attenuated pediatric RSV vaccines

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
                                                    Boost at 12-15 months
            at 4 or 6 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          * RSV Seronegative Children 6-24 Months, n = ~30 to 51
population:
                                                                             (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        NS1 NS2        N     P     M    SH   G         F            M2              L

                            cp                              cp cp                  cp                    cp
                                                  SH                                    248      1030
                                                                        404
   (P1114)                                                                               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

  RSV ∆NS2/        NS1 NS2       N     P      M   SH    G           F         M2               L

   ∆1313/
                        NS2
   I1314L                                                                                     ∆1313     I1314L
                 • Deletion of IFN antagonist may provide increased immunogenicity

   (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

                 • Deletion of RNA regulatory protein:
RSV LID M2-2:                        Increased antigen expression may increase immunogenicity
  IMPAACT        • Expect gene deletion to be highly stable
    2000         • 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 cps2 P1114                   Projected studies:
              seroneg. 6‐24 mo
                                              1. Expanded study with
                                              lead
RSV MEDI ∆M2‐2 CIR        RSV LID ∆M2‐2       candidate identified from
                          IMPAACT 2000        the 2013/2014 studies
seroneg. 6‐24 mo
                          seroneg. 6‐24 mo
                                              2. Modified RSV candidate

                                              3. Bovine/human PIV3
RSV ∆NS2∆1313 CIR         RSV ∆NS2∆1313 CIR   vector expressing RSV F
seropos. 12‐59 mo         seroneg. 6‐24 mo

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.