Summary

Name:

RSV-F VLP vaccine

Synonyms:

RSV vaccine; RSV F-VLP vaccine; RSV F VLP vaccine; RSV F vaccine

Sponsor:

Novavax (USA) (formerly DynCorp)

Type of product:

Vaccine

Viral family:

Paramyxoviridae

Status:

Phase III
New Phase II initiated after failure of a Phase III trial, Jan. 2017; Fast track designation granted by FDA (2016); See Remarks

RSV-F VLP vaccine 

Synonyms:RSV vaccine; RSV F-VLP vaccine; RSV F VLP vaccine; RSV F vaccine       Sponsor:Novavax (USA) (formerly DynCorp)       Type of product:Vaccine       Mode of action:Recombinant protein vaccine       Viral family:Paramyxoviridae       Virus:RSV (Respiratory Syncytial virus)      

Details

Characteristics:

Based on VLP (virus-like particle) technology, consisting in proprietary matrix protein forming 3D structure nanoparticle, designed to carry RSV fusion protein "F" (post-fusion stable conformation) on its surface to elicit specific immune response;

Developed as vaccine for infants via maternal immunization;

 

Modifications have been introduced to ensure that the recombinant viral F-protein in the vaccine is properly folded and more stable than the native (pre-fusion) F protein in the viral envelope

 

Ref.: Sponsor's website; Fries et al., Immun Ageing. 2017 Apr 12;14:8; August et al., Vaccine. 2017 Jun 27;35(30):3749-3759

PK Data, Dosage or Route of Administration:

Administration by injection

In vivo and clinical data:

In preclinical studies, mice were injected twice with 10 µg/dose of VLPs with and without adjuvant, and compared to inoculation of inactivated or live RSV virions, or placebo:

  • Highest titer of neutralizing antibodies was obtained with VLPs/adjuvant group
  • VLPs induced antibody titers higher than those obtained with live RSV or inactivated RSV
  • VLPs induced strong cell-mediated immune responses with activation of CD8+ cytotoxic T-cells against viral F protein
  • VLP-inoculated mice had reduced amounts of RSV in their lungs after challenge with live virus

 

On Apr. 2, 2013, Novavax announced top-line results of Phase II dose-ranging clinical trial (NCT01704365) conducted in in women of childbearing age:

  • Trial was a randomized, blinded, placebo-controlled study evaluating safety and immunogenicity of two-dose levels (60 µg and 90 µg) of nanoparticle vaccine with and without aluminum phosphate (alum) as adjuvant, in 330 women of childbearing age
  • Vaccine was administered IM as either 1 or 2 injections of vaccine or placebo, at study day 0 and day 28, with safety and immunogenicity evaluated over a period of 6 months and 4 months, respectively
  • Vaccine was well-tolerated and without any vaccine-related SAEs, with only transient mild to moderate injection site pain, more frequent in adjuvanted vaccine recipients, and mild to moderate headache, fatigue and muscle ache
  • IgG antibodies to viral F protein in serum rose 6 to16-fold across both 60 and 90 μg doses, with adjuvant enhancing immune response
  • More specifically, peak geometric mean titers of anti-F IgG in the two-dose alum groups ranged from 12,000-14,000 representing a 13 to 16-fold rise, compared to a 6 to10-fold rise in the non-alum groups; minimal increases were observed by increasing the doses (60 to 90 μg)
  • Peak geometric mean RSV A neutralizing antibodies in the alum groups ranged from 9.5-10.5 log2, representing a 3.1 to 3.8-fold rise
  • Neutralizing antibody responses were seen with both doses and with similar magnitude following first or second vaccinations

 

On Aug. 10, 2015, Novavax announced top-line results from Phase II study conducted in older adults (60 years of age or older):

  • Phase II trial initiated in Oct. 2014 was randomized, observer-blinded, placebo-controlled study done with 1600 older adults in US during 2014-2015 RSV season, who received 135 µg dose of vaccine w/o adjuvant
  • Among subjects receiving vaccine (N=759), there were 21 cases of symptomatic RSV infection, compared to 38 cases in placebo group (N=771), representing 43.9% efficacy
  • Among subjects receiving vaccine, there were 19 cases of RSV-associated lower respiratory tract infections, compared to 36 cases in placebo group, representing 46.4% efficacy (p=0.03)
  • Among subjects receiving vaccine, there was a durable 4.8-fold increase in anti-F IgG response (vs. day 0) at days 14, 28 and 56, with immune response observed in over 93% of subjects; Antibody titers peaked at day 14 post-vaccination, plateaued at day 28 and remained at elevated levels through day 56 (last measurement)
  • Safety profile in vaccine group was nearly identical to that of placebo group

 

On Sep. 29, 2015, Novavax announced top-line data from ongoing Phase II trial NCT02247726:

  • Trial was randomized, blinded, placebo-controlled study in which 50 healthy pregnant women in their third trimester were randomized to receive either placebo or 120 µg of RSV F Vaccine adjuvanted with 0.4 mg of aluminum phosphate
  • Subjects were followed through remainder of their pregnancies, delivery and for an additional 180 days postpartum to assess safety and immunogenicity as measured by serum RSV anti-F IgG, microneutralizing, and Palivizumab-competing antibody titers; Upon delivery, umbilical cord blood samples were obtained to determine titers of RSV Palivizumab-competing antibody, anti-F IgG, and microneutralizing titers in newborns, and additional serum samples from the infant participants were obtained over the following 6-month period to provide preliminary estimate of half-life of vaccine-induced maternal antibodies
  • Women in vaccinated group demonstrated a geometric mean 14-fold rise in anti-F IgG, 29-fold rise in Palivizumab-competing antibody, and 2-fold rise in microneutralization titers, while women who received placebo demonstrated no significant change in their antibody levels
  • At delivery, geometric mean anti-F IgG antibody titer in immunized women was 7,244 Elisa Units and on average, the infants' antibody titer equaled 100% of the mothers' anti-F IgG antibody titer; The geometric mean Palivizumab-competing antibody titer was 212 µg/mL in immunized mothers and the average Palivizumab-competing antibody transfer within the mother-infant pairs was 90%
  • Geometric mean microneutralizing antibody titers in immunized mothers were 759 and 481 µg/mL for RSV/A and RSV/B respectively, and average microneutralizing antibody transfer within mother-infant pairs was 90% for RSV/A and 100% for RSV/B
  • Estimated half-lives of infant Palivizumab-competing antibody, anti-F IgG, RSV/A and RSV/B microneutralizing antibodies, based on data through day 60, were 41, 30, 36 and 34 days, respectively

 

On Sept. 15, 2016, Novavax announced topline data from Phase III Resolve™ clinical trial of its RSV F Vaccine in older adults:

  • Phase III Resolve™ trial was a randomized, observer-blinded, placebo-controlled trial that enrolled 11,856 older adults (60 years of age and older)
  • Primary objective was efficacy in prevention of moderate-to-severe RSV-associated lower respiratory tract disease, and secondary objective was efficacy of the vaccine in reducing incidence of all symptomatic respiratory disease due to RSV
  • Results in regards of Primary objective: among 5935 individuals who received the placebo, 26 (0.44%) showed moderate-to-severe RSV-associated lower respiratory tract disease, compared to 28 out of 5921 individuals (0.47%) who received the vaccine; Vaccine efficacy was evaluated as -7.9% (CI: -84, 37); p=0.78, not significant
  • Results in regards of Secondary objective: among 5935 individuals who received the placebo, 117 (1.97%) showed symptomatic respiratory disease due to RSV, compared to 102 out of 5921 individuals (1.72%) who received the vaccine; Vaccine efficacy was evaluated as 12.6% (CI: -14, 33); p=0.32, not significant
  • Vaccine was well tolerated

 

On Jul. 24, 2017, Novavax announced topline data from its Phase II safety and immunogenicity trial NCT03026348 (E205) of the RSV-F Vaccine in older adults:

  • Objective of the Phase II randomized, observer-blinded, placebo-controlled trial was to assess safety and immunogenicity of one and two-dose regimens of the RSV-F Vaccine, with and without aluminum phosphate or Novavax’ proprietary Matrix-M™ adjuvant, in 300 older adults who were enrolled and vaccinated outside of the RSV season to best assess immunogenicity of the treatment arms
  • Immunogenicity outcomes indicate both aluminum phosphate and Matrix-M adjuvants significantly increased the magnitude, duration and quality of the immune response relative to a control of 135 µg dose of the RSV-F antigen alone (the formulation used in the prior Phase III older adults efficacy study)
  • Similarly, two-dose regimens significantly increased immune responses and suggests two doses of the RSV-F Vaccine with adjuvant may augment durability of the immune response to the vaccine
  • According to the sponsor, the data strongly support the inclusion of adjuvanted formulations of the RSV-F Vaccine in future older adult trials
  • All formulations and regimens were safe and well-tolerated

Development status

Phase III
New Phase II initiated after failure of a Phase III trial, Jan. 2017; Fast track designation granted by FDA (2016); See Remarks

Remarks

Vaccine for Respiratory Syncytial virus;
Program based on concept of maternal immunization as an approach to protect infants from RSV infection;
 

A collaboration with University of Massachusetts Medical School has been set up to work on a distinct RSV vaccine based on the viral G glycoprotein;

 

Novavax received in Oct. 2009 a grant from NIAID to pursue vaccine development;

 

In Nov. 2010, Novavax had to put on clinical hold its Phase I trial of the vaccine following request from FDA for additional information regarding chemistry, manufacturing and controls;

On Dec. 16, 2010 Novavax announced that Phase I trial of the vaccine had resumed under FDA authorization;

Funding for Phase II provided in part by PATH;

 

On Nov. 20, 2014, Novavax announced that the FDA granted Fast Track Designation to its RSV F-Protein nanoparticle vaccine candidate for protection of infants via maternal immunization;

 

At the same time Novavax announced Phase II data of the vaccine in pregnant women in Sep. 2015, the sponsor also announced that it has been awarded a grant of up to $89 million by the Bill & Melinda Gates Foundation to support development of the vaccine Phase III clinical trial in pregnant women;

 

On May 25, 2016, Novavax announced that the FDA has granted Fast Track Designation to RSV F Vaccine for protection of older adults (60 years of age and older);

 

In Sep. 2016, sponsor announced that Phase III Resolve™ trial did not meet the pre-specified primary objective (defined as the efficacy in preventing moderate-severe RSV-associated lower respiratory tract disease) or the secondary efficacy objective (reduction in the incidence of all symptomatic respiratory disease due to RSV), and did not demonstrate vaccine efficacy (see Clinical Data);

 

On Jan. 19, 2017, Novavax announced via Press release the initiation of a Phase II clinical trial of its RSV F Vaccine in older adults (60 years of age and older), to assess safety and immunogenicity to one and two dose regimens of the RSV F vaccine, with and without aluminum phosphate or Novavax’ proprietary Matrix-M™ adjuvant, in older adults;

 

As of Mar. 2018, the "Prepare" trial evaluating the vaccine efficacy at preventing RSV infection in infants via maternal immunization is ongoing