Background. Respiratory syncytial virus (RSV) is a leading cause of infant morbidity and mortality. A recombinant RSV fusion protein nanoparticle vaccine (RSV F vaccine) candidate for maternal ...immunization was tested for safety and immunogenicity in women of childbearing age. Methods. Three hundred thirty women (18–35 years) were randomized to receive 1 or 2 doses of RSV F vaccine (60 or 90 μg) with or without aluminum phosphate adjuvant, or placebo at days 0 and 28. Safety was evaluated over 180 days; immunogenicity and RSV infection rates were evaluated over 112 days. Results. All vaccine formulations were well tolerated, without vaccine-related serious adverse events. Anti-F immunoglobulin G antibodies rose 6.5–15.6-fold, with significantly higher levels in 2-dose, adjuvanted regimens at day 56. Palivizumab-competitive antibody levels were undetectable at day 0 but increased up to 325 μg/mL at day 56. A 2.7- and 3.5-fold rise in RSV/A and RSV/B microneutralization antibodies were noted at day 56. Between days 56 and 112, 21% (12/56) of placebo recipients and 11% of vaccinees (26/244) showed evidence of a recent RSV infection (P = .04). Conclusions. The vaccine appeared safe, immunogenic, and reduced RSV infections. Further development as a vaccine for use in maternal immunization is warranted. Clinical Trials Registration. NCT01704365.
Abstract Objective Respiratory syncytial virus (RSV) causes significant morbidity and mortality in infants. We are developing an RSV fusion (F) protein nanoparticle vaccine for immunization of third ...trimester pregnant women to passively protect infants through transfer of RSV-specific maternal antibodies. The present trial was performed to assess the immunogenicity and safety of several formulations of RSV F vaccine in 1-dose or 2-dose schedules. Methods Placebo, or vaccine with 60 μg or 120 μg RSV F protein and 0.2, 0.4, or 0.8 mg aluminum, were administered intramuscularly on Days 0 and 28 to healthy women 18–35 years old. Immunogenicity was assessed from Days 0 through 91 based on anti-F IgG and palivizumab-competitive antibody (PCA) by ELISA, and RSV A and B neutralizing antibodies by microneutralization (MN) assay. Solicited adverse events were collected through Day 7 and unsolicited adverse events through Day 91. Results All formulations were well-tolerated, with no treatment-related serious adverse events. Anti-F IgG and PCA responses were correlated and increased after both doses, while MN increased significantly only after the first dose, then plateaued. The timeliest and most robust antibody responses followed one dose of 120 μg RSV F protein and 0.4 mg aluminum, but persistence through 91 days was modestly (∼25%) superior following two doses of 60 μg RSV F protein and 0.8 mg aluminum. Western blot analysis showed RSV infections in active vaccinees were reduced by 52% overall (p = 0.009 overall) over the Day 0 through 90 period. Conclusions RSV F nanoparticle vaccine formulations were well tolerated and immunogenic. The optimal combination of convenience and rapid response for immunization in the third trimester occurred with 120 μg RSV F and 0.4 mg aluminum, which achieved peak immune responses in 14 days and sufficient persistence through 91 days to allow for passive transfer of IgG antibodies to the fetus. NCT01960686.
Abstract
Background
Respiratory syncytial virus (RSV) is the leading cause of infant lower respiratory tract disease and hospitalization worldwide.
Methods
Safety and immunogenicity of RSV fusion (F) ...protein nanoparticle vaccine or placebo were evaluated in 50 healthy third-trimester pregnant women. Assessments included vaccine tolerability and safety in women and infants, and RSV-specific antibody measures in women before and after vaccination, at delivery and post partum.
Results
The vaccine was well tolerated; no meaningful differences in pregnancy or infant outcomes were observed between study groups. RSV-specific antibody levels increased significantly among vaccine recipients, including responses competitive with well-described monoclonal antibodies specific for multiple RSV neutralizing epitopes. No significant antibody increase was seen among placebo recipients, although a shallow upward trend across the RSV season was noted. Transplacental antibody transfer was 90%–120% across assays for infants of vaccinated women. Women with an interval of ≥30 days between vaccination and delivery demonstrated higher placental antibody transfer rates than women with an interval <30 days. Half-lives of RSV-specific antibodies in infants approximated 40 days. There was no evidence of severe RSV disease in infants of vaccinated mothers.
Conclusions
Data from this phase 2 study support a maternal immunization strategy to protect infants from RSV disease.
Clinical Trials Registration
NCT02247726.
Immunization of pregnant women with an RSV F protein nanoparticle vaccine was well-tolerated by the women and their infants, and produced antibody responses that were transferred via the placenta and exhibited a half-life of approximately 40 days in infants.
Highlights ► This Phase 1 trial evaluated the safety and immunogenicity of an RSV (F) nanoparticle vaccine. ► The vaccine was well-tolerated and no related SAEs were observed. ► Both RSV A and B ...microneutralizating antibodies were increased in vaccinees versus placebo. ► There was a 7- to 19-fold increase in anti-F IgG and a 7- to 24-fold increase in palivizumab-like antibodies. ► The levels of immunity are similar to those seen in other settings with decreased hospitalizations.
A preventative strategy for Respiratory Syncytial Virus (RSV) infection constitutes an under-recognized unmet medical need among older adults. Four formulations of a novel recombinant RSV F ...nanoparticle vaccine (60 or 90 μg RSV F protein, with or without aluminum phosphate adjuvant) administered concurrently with a licensed inactivated trivalent influenza vaccine (TIV) in older adult subjects were evaluated for safety and immunogenicity in this randomized, observer-blinded study.
A total of 220 healthy males and females ≥ 60 years of age, without symptomatic cardiopulmonary disease, were vaccinated concurrently with TIV and RSV F vaccine or placebo. All vaccine formulations produced an acceptable safety profile, with no vaccine-related serious adverse events or evidence of systemic toxicity. Vaccine-induced immune responses were rapid, rising as early as 7 days post-vaccination; and were comparable in all formulations in terms of magnitude, with maximal levels attained within 28 (unadjuvanted) or 56 (adjuvanted) days post-vaccination. Peak anti-F protein IgG antibody levels rose 3.6- to 5.6-fold, with an adjuvant effect observed at the 60 μg dose, and a dose-effect observed between the unadjuvanted 60 and 90 μg regimens. The anti-F response persisted through 12 months post-vaccination. Palivizumab-competitive antibodies were below quantifiable levels (<33 μg/mL) at day 0. The rise of antibodies with specificity for Site II peptide, and the palivizumab-competitive binding activity, denoting antibodies binding at, or in proximity to, antigenic Site II on the F protein, closely paralleled the anti-F response. However, a larger proportion of antibodies in adjuvanted vaccine recipients bound to the Site II peptide at high avidity. Day 0 neutralizing antibodies were high in all subjects and rose 1.3- to 1.7-fold in response to vaccination. Importantly, the RSV F vaccine co-administered with TIV did not impact the serum hemagglutination inhibition antibody responses to a standard-dose TIV, and TIV did not impact the immune response to the RSV F vaccine.
RSV F protein nanoparticle vaccine induced increases in measures of functional immunity to RSV in older adults and demonstrated an acceptable safety profile. Adjuvanted formulations provided additional immunogenicity benefit as compared to increasing antigen dose alone. This trial was registered with ClinicalTrials.gov number NCT01709019.
An effective vaccine for respiratory syncytial virus (RSV) is an unrealized public health goal. A single dose of the prefusion-stabilized fusion (F) glycoprotein subunit vaccine (DS-Cav1) ...substantially increases serum-neutralizing activity in healthy adults. We sought to determine whether DS-Cav1 vaccination induces a repertoire mirroring the pre-existing diversity from natural infection or whether antibody lineages targeting specific epitopes predominate. We evaluated RSV F-specific B cell responses before and after vaccination in six participants using complementary B cell sequencing methodologies and identified 555 clonal lineages. DS-Cav1-induced lineages recognized the prefusion conformation of F (pre-F) and were genetically diverse. Expressed antibodies recognized all six antigenic sites on the pre-F trimer. We identified 34 public clonotypes, and structural analysis of two antibodies from a predominant clonotype revealed a common mode of recognition. Thus, vaccination with DS-Cav1 generates a diverse polyclonal response targeting the antigenic sites on pre-F, supporting the development and advanced testing of pre-F-based vaccines against RSV.
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•DS-Cav1 vaccination boosts diverse B cell lineages recognizing the pre-F form of RSV F•Vaccine-induced antibody lineages target all known antigenic sites on RSV F•RSV F-specific B cell sequencing identifies numerous pre-F-specific public clonotypes•Structural analysis of a site V public clonotype reveals common mode of recognition
A single dose of the prefusion-stabilized fusion (F) glycoprotein subunit vaccine (DS-Cav1) increases serum neutralizing activity in healthy adults. Mukhamedova et al. evaluated RSV F-specific B cell responses before and after vaccination and reveal that DS-Cav1 generates a diverse polyclonal response targeting the antigenic sites on pre-F, supporting the development and advanced testing of pre-F-based vaccines against RSV.
Highlights ► The safety and immunogenicity of one or two doses of a recombinant A (H1N1) 2009 influenza VLP vaccine was evaluated in a two-stage, Phase 2, randomized, double-blind, placebo-controlled ...study conducted during the H1N1 2009 pandemic in Mexico. ► The H1N1 2009 VLP vaccine was safe and well-tolerated with no vaccine-related serious adverse events. ► The VLP vaccine groups demonstrated robust HAI immune responses after a single vaccination, which were statistically higher compared to placebo.
Technologies that define the atomic-level structure of neutralization-sensitive epitopes on viral surface proteins are transforming vaccinology and guiding new vaccine development approaches. ...Previously, iterative rounds of protein engineering were performed to preserve the prefusion conformation of the respiratory syncytial virus (RSV) fusion (F) glycoprotein, resulting in a stabilized subunit vaccine candidate (DS-Cav1), which showed promising results in mice and macaques. Here, phase I human immunogenicity data reveal a more than 10-fold boost in neutralizing activity in serum from antibodies targeting prefusion-specific surfaces of RSV F. These findings represent a clinical proof of concept for structure-based vaccine design, suggest that development of a successful RSV vaccine will be feasible, and portend an era of precision vaccinology.
Malaria is a major cause of illness worldwide. In a phase 2 trial in Mali, one subcutaneous dose of L9LS, a monoclonal antibody targeting
Plasmodium falciparum
, reduced the incidence of clinical ...malaria among children.
Abstract Background Protection of newborns and young infants against RSV disease via maternal immunization mediated by transplacental transfer of antibodies is under evaluation in third-trimester ...pregnant women with the RSV recombinant F nanoparticle vaccine (RSV F vaccine). Since the hemichorial placental architecture in guinea pigs and humans is similar, the guinea pig model was employed to assess RSV F vaccine immunogenicity in pregnant sows and to compare RSV-specific maternal antibody levels in their pups. Methods Thirty (30) presumptive pregnant guinea pigs were immunized on gestational day 25 and 46 with placebo (PBS), 30 μg RSV F, or 30 μg RSV F + 400 μg aluminum phosphate. Sera at delivery/birth (sows/pups) and 15 and 30 days post-partum (pups) were analyzed for the presence of anti-F IgG, palivizumab-competitive antibody (PCA) and RSV/A microneutralization (MN). Results The rates of pregnancy and stillbirth were similar between controls and vaccinees. The vaccine induced high levels of anti-F IgG, PCA and MN in sows, with the highest levels observed in adjuvanted vaccinees. Placental transfer to pups was proportional to the maternal antibody levels, with concentration effects observed for all immune measures. Conclusions The RSV F vaccine was safe and immunogenic in pregnant guinea pigs and supported robust transplacental antibody transfer to their pups. Relative concentration of antibodies in the pups was observed even in the presence of high levels of maternal antibody. Guinea pigs may be an important safety and immunogenicity model for preclinical assessment of candidate vaccines for maternal immunization.
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