Pneumococcal conjugate vaccines (PCVs) have significantly decreased pneumococcal disease worldwide; however, expanding serotype coverage may further reduce disease burden. A 20-valent PCV (PCV20) ...containing capsular polysaccharide conjugates of serotypes present in the 13-valent PCV (PCV13) and 7 new serotypes (8, 10A, 11A, 12F, 15B, 22F, and 33F) is currently in development. This phase 2 study evaluated safety, tolerability, and immunogenicity of PCV20 in adults without prior pneumococcal vaccination.
In this randomized, active-controlled, double-blinded trial, 444 adults 60 through 64 years of age were randomized to receive either a single dose of PCV20 followed 1 month later by saline placebo or a single dose of PCV13 followed 1 month later by 23-valent polysaccharide vaccine. Local injection site reactions, select systemic symptoms, and adverse events (AEs) were recorded. Immunogenicity was assessed by measuring serotype-specific opsonophagocytic activity (OPA) titers before and approximately 1 month after each vaccination.
Local reaction and systemic event rates were similar after vaccination with PCV20 or PCV13; no serious vaccine-related AEs were reported. In the PCV20 group, functional immune responses as measured by OPA were robust for all 20 serotypes included in the vaccine, with geometric mean fold rises from baseline ranging from 6.0 to 113.4.
PCV20 was well tolerated in adults 60 to 64 years of age, with a safety profile consistent with historical experience of PCVs in this age group. Substantial OPA responses were elicited against all serotypes. Results demonstrate the potential for PCV20 to expand pneumococcal disease protection.
NCT03313037.
An effective vaccine is needed to halt the spread of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic. Recently, we reported safety, tolerability and antibody response data ...from an ongoing placebo-controlled, observer-blinded phase I/II coronavirus disease 2019 (COVID-19) vaccine trial with BNT162b1, a lipid nanoparticle-formulated nucleoside-modified mRNA that encodes the receptor binding domain (RBD) ofthe SARS-CoV-2 spike protein1. Here we present antibody and T cell responses after vaccination with BNT162b1 from a second, non-randomized open-label phase I/II trial in healthy adults, 18-55 years of age. Two doses of 1-50 pg ofBNT162b1 elicited robust CD4+ and CD8+ T cell responses and strong antibody responses, with RBD-binding IgG concentrations clearly above those seen in serum from a cohort of individuals who had recovered from COVID-19. Geometric mean titres of SARS-CoV-2 serum-neutralizing antibodies on day 43 were 0.7-fold (1-pg dose) to 3.5-fold (50-pg dose) those of the recovered individuals. Immune sera broadly neutralized pseudoviruses with diverse SARS-CoV-2 spike variants. Most participants had T helper type 1 (TH1)-skewed T cell immune responses with RBD-specific CD8+ and CD4+ T cell expansion. interferon-у was produced by a large fraction ofRBD-specific CD8+ and CD4+ T cells. The robust RBD-specific antibody, T cell and favourable cytokine responses induced by the BNT162b1 mRNA vaccine suggest that it has the potential to protect against COVID-19 through multiple beneficial mechanisms.
Group B streptococcus (GBS) is a major cause of invasive disease in young infants. Infants born to women with sufficient pre-existing anti-GBS capsular IgG antibodies are at reduced risk of GBS ...disease, making maternal immunisation a potential strategy for prevention. We aimed to assess the safety and immunogenicity of a novel hexavalent (serotypes Ia, Ib, II, III, IV, and V) GBS conjugate vaccine (GBS6).
This phase 1/2, placebo-controlled, observer-blinded, dose-escalation trial, was done at four clinical research centres in the USA (Kentucky, Georgia, and two sites in Utah). Healthy, non-pregnant adults aged 18–49 years were randomly assigned using an interactive, web-based response technology system. Within each dose group (low, medium, or high), participants in sentinel cohorts were randomly assigned 2:2:1 and expanded cohort participants were randomly assigned 4:4:1 to receive GBS6 with aluminium phosphate (AlPO4), GBS6 without AlPO4, or placebo (saline control). One 0·5 mL dose of either saline placebo or 5 μg capsular polysaccharide per serotype in the low-dose group, 10 μg capsular polysaccharide per serotype in the medium-dose group, or 20 μg capsular polysaccharide per serotype in the high-dose group was administered by intramuscular injection into the deltoid muscle on day 1. The primary outcome was safety up to 6 months after vaccination, including the proportion of sentinel cohort participants with clinical laboratory abnormalities at 1 week, the proportion of all participants reporting solicited local reactions, systemic events, or use of antipyretic or pain medication within 14 days, adverse events up to 1 month, and medically attended or serious adverse events up to 6 months. The secondary outcome was GBS immunogenicity (serotype-specific IgG geometric mean concentrations at 1 month). This study is registered with ClinicalTrials.gov, NCT03170609.
Between June 5, 2017, and June 25, 2018, 365 participants were randomly assigned and 364 (52 in each dose group) were vaccinated and included in the safety analysis. Unsolicited adverse events were reported by 15 (29%) participants in the 5 μg with AlPO4 group, 13 (25%) in the 5 μg without AlPO4 group, 22 (42%) in the 10 μg with AlPO4 group, 12 (23%) in the 10 μg without AlPO4 group, 25 (48%) in the 20 μg with AlPO4 group, 21 (40%) in the 20 μg without AlPO4 group, and 20 (38%) in the placebo group. The most common unsolicited adverse events were in the system organ class of infections and infestations in any dose or formulation of GBS6 (ranging from six 12% in the 10 μg without AlPO4 group to 15 29% in the 20 μg with AlPO4 group and placebo group). Three participants reported at least one serious adverse event during the study, one each in the 5 μg GBS6 with AlPO4 group (diabetic ketoacidosis, two events; resolved), 10 μg GBS6 with AlPO4 group (died by suicide), and 20 μg GBS6 with AlPO4 group (metrorrhagia; resolved). None of these serious adverse events were considered related to the vaccine. 11 of the 365 participants were excluded from the evaluable immunogenicity population, including one participant who did not receive the vaccine, and ten who at 1 month after vaccination were withdrawn for various reasons. GBS serotype-specific IgG geometric mean concentrations increased by 1 week after vaccination for all GBS6 groups, peaked at 2 weeks, stabilised by 1 month, and declined gradually but remained higher than placebo at 6 months.
GBS6 was well tolerated in healthy adults and elicited robust immune responses for all dose levels and formulations that persisted 6 months after vaccination. This study supports further evaluation of GBS6 in pregnant women.
Pfizer.
Abstract
Background
Pneumococcal conjugate vaccines (PCVs) have significantly reduced pneumococcal disease, but disease from non-PCV serotypes remains. The safety, tolerability, and immunogenicity of ...a 20-valent PCV (PCV20) were evaluated.
Methods
This pivotal phase 3, randomized, double-blind study enrolled adults into 3 age groups (≥60, 50–59, and 18–49 years) at US and Swedish sites. Participants were randomized to receive 1 PCV20 or 13-valent PCV (PCV13) dose. After 1 month, participants aged ≥60 years also received 1 dose of saline or 23-valent polysaccharide vaccine (PPSV23). Safety assessments included local reactions, systemic events, adverse events, serious adverse events, and newly diagnosed chronic medical conditions. Opsonophagocytic activity geometric mean titers 1 month after PCV20 were compared with 13 matched serotypes after PCV13 and 7 additional serotypes after PPSV23 in participants aged ≥60 years; noninferiority was declared if the lower bound of the 2-sided 95% confidence interval for the opsonophagocytic activity geometric mean titer ratio (ratio of PCV20/saline to PCV13/PPSV23 group) was >0.5. PCV20-elicited immune responses in younger participants were also bridged to those in 60–64-year-olds.
Results
The severity and frequency of prompted local reactions and systemic events were similar after PCV20 or PCV13; no safety concerns were identified. Primary immunogenicity objectives were met, with immune responses after PCV20 noninferior to 13 matched serotypes after PCV13 and to 6 additional PPSV23 serotypes in participants aged ≥60 years; serotype 8 missed the statistical noninferiority criterion. PCV20 induced robust responses to all 20 vaccine serotypes across age groups.
Conclusions
PCV20 was safe and well tolerated, with immunogenicity comparable to that of PCV13 or PPSV23. PCV20 is anticipated to expand protection against pneumococcal disease in adults.
Clinical Trials Registration
NCT03760146.
•A phase 3 study in adults ≥65 years of age with prior pneumococcal vaccination.•Safety and immunogenicity of PCV20 were described in this population.•PCV20 safety and tolerability were similar ...across different vaccine histories.•PCV20 induced immune responses to all vaccine serotypes regardless of prior vaccine.
A 20-valent pneumococcal conjugate vaccine, PCV20, was developed to expand protection against vaccine-preventable pneumococcal disease. PCV20 contains the components of the 13-valent pneumococcal conjugate vaccine, PCV13, and includes capsular polysaccharide conjugates for 7 additional serotypes. Thus, PCV20 may cover those additional serotypes in individuals previously vaccinated with PCV13 or provide benefits of immunization with a conjugate vaccine to individuals previously immunized with a pneumococcal polysaccharide vaccine. This study described the safety and immunogenicity of PCV20 in adults ≥65 years of age with prior pneumococcal vaccination.
This phase 3, multicenter, randomized, open-label study was conducted in the United States and Sweden. Adults ≥65 years of age were enrolled into 1 of 3 cohorts based on their prior pneumococcal vaccination history (23-valent pneumococcal polysaccharide vaccine PPSV23, PCV13, or both PCV13 and PPSV23). Participants were randomized 2:1 within their cohort to receive a single dose of PCV20 or PCV13 in those with prior PPSV23 only, and PCV20 or PPSV23 in those with prior PCV13 only; all participants with prior PCV13 and PPSV23 received PCV20. Safety was assessed by prompted local reactions within 10 days, systemic events within 7 days, adverse events (AEs) within 1 month, and serious AEs (SAEs) and newly diagnosed chronic medical conditions (NDCMCs) within 6 months after vaccination. Immune responses 1 month after PCV20 were assessed.
The percentages of participants reporting local reactions, systemic events, and AEs after PCV20 administration were similar across cohorts and comparable with the PCV13 and PPSV23 control groups. SAE and NDCMC rates were low in all groups. Robust immune responses, including opsonophagocytic antibody responses, to the 20 vaccine serotypes were observed 1 month after PCV20 regardless of prior pneumococcal vaccination.
PCV20 was well tolerated and immunogenic in adults ≥65 years of age previously vaccinated with different pneumococcal vaccine regimens.
Clinicaltrials.gov NCT03835975.
•This was a phase 3 randomized, double-blind PCV20 study in adults 18–49 years old.•The immunogenicity of 3 PCV20 lots was evaluated and safety of PCV20 was described.•Equivalence of vaccine ...responses was observed for 20 serotypes across 3 PCV20 lots.•All of the PCV20 lots elicited robust immune responses to the vaccine serotypes.•Safety and tolerability of PCV20 was acceptable and similar to PCV13.
Introduction of pneumococcal conjugate vaccines (PCVs), including the 13-valent PCV (PCV13), has considerably reduced pneumococcal disease burden. However, additional serotypes not in PCV13 continue to present a substantial disease burden. The 20-valent PCV (PCV20) was developed to expand protection against pneumococcal disease beyond PCV13. As part of the phase 3 clinical development program, the current study assessed consistency of immune responses across 3 lots of PCV20 and described the safety profile of PCV20.
This phase 3, randomized, multicenter, double-blind study of pneumococcal vaccine-naive adults 18–49 years of age randomized 1710 participants in a 2:2:2:1 ratio to receive 1 of 3 lots of PCV20 or PCV13. Immunogenicity was assessed through serotype-specific opsonophagocytic activity (OPA) titers before and approximately 1 month (28–42 days) after vaccination. Reported local reactions within 10 days, systemic events within 7 days, adverse events (AEs) within 30 days, and serious AEs (SAEs) and newly diagnosed chronic medical conditions (NDCMCs) within 6 months after vaccination were evaluated.
Equivalence in immune responses (OPA geometric mean titers) for all 20 vaccine serotypes was demonstrated across the 3 PCV20 lots. Robust responses, assessed by OPA geometric mean fold rises, percentage of participants achieving ≥4-fold rises, and percentage of participants with OPA titers ≥lower limit of quantitation, were observed after PCV20. Reported rates of local reactions, systemic events, and AEs were similar between the pooled PCV20 lots and PCV13; most events were mild or moderate. Reported rates of SAEs and NDCMCs were low and similar between the PCV20 and PCV13 groups.
Three different lots of PCV20 demonstrated robust and consistent immunogenicity. The safety and tolerability of PCV20 was acceptable and similar to that of PCV13. (Clinicaltrials.gov: NCT03828617).
Highlights • Staphylococcus aureus causes serious, life-threatening infections. • Increasing antibiotic resistance has driven the search for alternate therapies. • No S. aureus vaccine approach has ...been successful thus far. • Approaches to solve issues surrounding S. aureus vaccine development are presented.
Abstract
Background
Group B streptococcus (GBS) causes serious diseases in newborn infants, often resulting in lifelong neurologic impairments or death. Prophylactic vaccination of pregnant women ...prior to delivery could provide comprehensive protection, as early onset and late-onset disease and maternal complications potentially could be addressed.
Methods
Capsular polysaccharide conjugate vaccine GBS6 was designed using surveillance data yielded by whole-genome sequencing of a global collection of recently recovered GBS isolates responsible for invasive neonatal GBS disease. Capsular polysaccharides were isolated, oxidized using sodium periodate, and conjugated to CRM197 by reductive amination in dimethyl sulfoxide. Immune responses in mice and rhesus macaques were measured in a multiplex Luminex immunoglobulin G (IgG) assay and opsonophagocytic activity assays.
Results
The optimized conjugates were immunogenic, alone and in combination, in mice and rhesus macaques, inducing IgG antibodies that mediated opsonophagocytic killing. Active immunization of murine dams with GBS6 prior to mating resulted in serotype-specific protection of pups from a lethal challenge with GBS. Protection following passive administration of serotype-specific IgG monoclonal antibodies to dams demonstrated conclusively that anticapsular polysaccharide IgG alone is sufficient for protection.
Conclusions
The findings support the ongoing clinical evaluation of maternal GBS6 vaccination as a potential alternative method to prevent GBS disease in infants.
Six-valent capsular polysaccharide conjugate vaccine GBS6 for the prevention of neonatal Group B Streptococcal (GBS) infections was evaluated in preclinical models. Vaccination with GBS6 or administration of serotype-specific IgG to pregnant dams protected pups against lethal challenges with GBS.
Staphylococcus aureus is both a commensal organism and also an important opportunistic human pathogen, causing a variety of community and hospital-associated pathologies, such as bacteremia-sepsis, ...endocarditis, pneumonia, osteomyelitis, arthritis and skin diseases. The resurgence of S. aureus during the last decade in many settings has been facilitated not only by bacterial antibiotic resistance mechanisms but also by the emergence of new S. aureus clonal types with increased expression of virulence factors and the capacity to neutralize the host immune response. Prevention of the spread of S. aureus infection relies on the use of contact precautions and adequate procedures for infection control that so far have not been fully effective. Prevention using a prophylactic vaccine would complement these processes, having the potential to bring additional, significant progress toward decreasing invasive disease due to S. aureus.
Staphylococcus aureus capsular polysaccharides (CP) are important virulence factors under evaluation as vaccine antigens. Clinical S. aureus isolates have the biosynthetic capability to express ...either CP5 or CP8 and an understanding of the relationship between CP genotype/phenotype and S. aureus epidemiology is valuable. Using whole genome sequencing, the clonal relatedness and CP genotype were evaluated for disease-associated S. aureus isolates selected from the Tigecycline Evaluation and Surveillance Trial (T.E.S.T) to represent different geographic regions in the United States (US) during 2004 and 2009-10. Thirteen prominent clonal complexes (CC) were identified, with CC5, 8, 30 and 45 representing >80% of disease isolates. CC5 and CC8 isolates were CP type 5 and, CC30 and CC45 isolates were CP type 8. Representative isolates from prevalent CC were susceptible to in vitro opsonophagocytic killing elicited by anti-CP antibodies, demonstrating that susceptibility to opsonic killing is not linked to the genetic lineage. However, as not all S. aureus isolates may express CP, isolates representing the diversity of disease isolates were assessed for CP production. While approximately 35% of isolates (primarily CC8) did not express CP in vitro, CP expression could be clearly demonstrated in vivo for 77% of a subset of these isolates (n = 20) despite the presence of mutations within the capsule operon. CP expression in vivo was also confirmed indirectly by measuring an increase in CP specific antibodies in mice infected with CP5 or CP8 isolates. Detection of antigen expression in vivo in relevant disease states is important to support the inclusion of these antigens in vaccines. Our findings confirm the validity of CP as vaccine targets and the potential of CP-based vaccines to contribute to S. aureus disease prevention.
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