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BCG vaccination provides incomplete protection against tuberculosis in infants. A new vaccine, modified Vaccinia Ankara virus expressing antigen 85A (MVA85A), was designed to enhance the protective efficacy of BCG. We aimed to assess safety, immunogenicity, and efficacy of MVA85A against tuberculosis and Mycobacterium tuberculosis infection in infants. In our double-blind, randomised, placebo-controlled phase 2b trial, we enrolled healthy infants (aged 4–6 months) without HIV infection who had previously received BCG vaccination. We randomly allocated infants (1:1), according to an independently generated sequence with block sizes of four, to receive one intradermal dose of MVA85A or an equal volume of Candida skin test antigen as placebo at a clinical facility in a rural region near Cape Town, South Africa. We actively followed up infants every 3 months for up to 37 months. The primary study outcome was safety (incidence of adverse and serious adverse events) in all vaccinated participants, but we also assessed efficacy in a protocol-defined group of participants who received at least one dose of allocated vaccine. The primary efficacy endpoint was incident tuberculosis incorporating microbiological, radiological, and clinical criteria, and the secondary efficacy endpoint was M tuberculosis infection according to QuantiFERON TB Gold In-tube conversion (Cellestis, Australia). This trial was registered with the South African National Clinical Trials Register (DOH-27-0109-2654) and with ClinicalTrials.gov on July 31, 2009, number NCT00953927 Between July 15, 2009, and May 4, 2011, we enrolled 2797 infants (1399 allocated MVA85A and 1398 allocated placebo). Median follow-up in the per-protocol population was 24·6 months (IQR 19·2–28·1), and did not differ between groups. More infants who received MVA85A than controls had at least one local adverse event (1251 [89%] of 1399 MVA85A recipients and 628 [45%] of 1396 controls who received the allocated intervention) but the numbers of infants with systemic adverse events (1120 [80%] and 1059 [76%]) or serious adverse events (257 [18%] and 258 (18%) did not differ between groups. None of the 648 serious adverse events in these 515 infants was related to MVA85A. 32 (2%) of 1399 MVA85A recipients met the primary efficacy endpoint (tuberculosis incidence of 1·15 per 100 person-years [95% CI 0·79 to 1·62]; with conversion in 178 [13%] of 1398 infants [95% CI 11·0 to 14·6]) as did 39 (3%) of 1395 controls (1·39 per 100 person-years [1·00 to 1·91]; with conversion in 171 [12%] of 1394 infants [10·6 to 14·1]). Efficacy against tuberculosis was 17·3% (95% CI −31·9 to 48·2) and against M tuberculosis infection was −3·8% (–28·1 to 15·9). MVA85A was well tolerated and induced modest cell-mediated immune responses. Reasons for the absence of MVA85A efficacy against tuberculosis or M tuberculosis infection in infants need exploration. Aeras, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium (OETC).

Streptococcus pyogenes (group A Streptococcus, Strep A) is a widespread pathogen that continues to pose a significant threat to human health. The development of a Strep A vaccine remains an unmet global health need. One of the major vaccine strategies is the use of M protein, which is a primary virulence determinant and protective antigen. Multivalent recombinant M protein vaccines are being developed with N-terminal M peptides that contain opsonic epitopes but do not contain human tissue cross-reactive epitopes. We completed a Phase I trial of a recombinant 30-valent M protein-based Strep A vaccine (Strep A vaccine, StreptAnova™) comprised of four recombinant proteins containing N-terminal peptides from 30 M proteins of common pharyngitis and invasive and/or rheumatogenic serotypes, adjuvanted with aluminum hydroxide. The trial was observer-blinded and randomized in a 2:1 ratio for intramuscular administration of Strep A vaccine or an alum-based comparator in healthy adult volunteers, at 0, 30 and 180 days. Primary outcome measures were assessments of safety, including assays for antibodies that cross-reacted with host tissues, and immunogenicity assessed by ELISA with the individual vaccine peptides and by opsonophagocytic killing (OPK) assays in human blood. Twenty-three Strep A-vaccinated participants and 13 controls completed the study. The Strep A vaccine was well-tolerated and there was no clinical evidence of autoimmunity and no laboratory evidence of tissue cross-reactive antibodies. The vaccine was immunogenic and elicited significant increases in geometric mean antibody levels to 24 of the 30 component M antigens by ELISA. Vaccine-induced OPK activity was observed against selected M types of Strep A in vaccinated participants that seroconverted to specific M peptides. The Strep A vaccine was well tolerated and immunogenic in healthy adults, providing strong support for further clinical development. [ClinicalTrials.gov NCT02564237].

Background. In the absence of an efficacious broadly protective vaccine, serogroup B Neisseria meningitidis (MenB) is the leading cause of bacterial meningitis and septicemia in many industrialized countries. An investigational recombinant vaccine that contains 3 central proteins; Neisserial adhesin A (NadA), factor H binding protein (fHBP) and Neisserial heparin binding antigen (NHBA) has been developed. These antigens have been formulated with and without outer membrane vesicles (rMenB+OMV and rMenB, respectively) from the New Zealand epidemic strain (B:4:P1.7–2,4). In this trial, we assessed the immunogenicity of these formulations in infants, who are at greatest risk of contracting MenB disease. Methods. A total of 147 infants from the United Kingdom were enrolled and randomly assigned to receive rMenB or rMenB+OMV at 2, 4, 6, and 12 months of age or a single dose at 12 months of age. Serum samples taken before and after vaccination were assayed in a standardized serum bactericidal antibody assay against 7 MenB strains. Local and systemic reactogenicity were recorded for 7 days after each vaccination. Analysis was according to protocol. Results. After 3 doses, both vaccines were immunogenic against strains expressing homologous or related NadA and fHBP. rMenB+OMV demonstrated greater immunogenicity than did rMenB and was immunogenic against strains expressing homologous PorA. Both vaccines elicited anamnestic responses after the fourth dose. For both vaccines, responses were lower against strains expressing heterologous fHBP variants and after a single dose at 12 months. Conclusions. The rMenB+OMV vaccine has the potential to protect infants from MenB disease, although the breadth of protection afforded to heterologous antigens requires additional investigation.

Increasing incidence rates, insufficient effectiveness of exposure prevention strategies, and the potential for serious outcomes despite antibiotic treatment highlight the need for a preventive vaccine against Lyme borreliosis. VLA15, an investigational Lyme borreliosis vaccine based on outer surface protein A (OspA) variants from clinically relevant Borrelia burgdorferi sensu lato genospecies in North America and Europe, has shown safety and immunogenicity in adults when administered with various three-dose schedules. We aimed to investigate the safety and immunogenicity of two-dose and three-dose schedules of VLA15 within a broader population, including children and adolescents, who are among those at increased risk of Lyme borreliosis. This randomised, observer-blind, placebo-controlled phase 2 trial is taking place at 14 clinical study centres in Lyme borreliosis-endemic areas in the USA. Healthy, eligible participants aged 5–65 years were enrolled in a 2:1:1 ratio to age cohorts of 18–65 years, 12–17 years, and 5–11 years through a staggered age-descending enrolment process. Within each age cohort, participants were randomly assigned with an electronic data capture system in a 1:1:1 ratio to receive intramuscular injections of 180 μg VLA15 at months 0, 2, and 6 (VLA15 M0-2-6 group); 180 μg VLA15 at months 0 and 6, and placebo at month 2 (VLA15 M0-6 group); or placebo at months 0, 2, and 6. Unmasked individuals included site staff and clinical research associates involved in randomisation and handling the investigational product, as well as specific individuals, both internal and external to the sponsor, who regularly reviewed trial safety data (including statisticians preparing relevant tables). All other individuals were masked; unmasking after the database snapshot for month 7 analyses for each age cohort was limited to the trial sponsor, collaboration partner, and statisticians. The primary immunogenicity endpoint was OspA serotype (ST)-specific IgG geometric mean titres (GMTs) assessed by ELISAs at month 7 (ie, 1 month after the third vaccination) and was evaluated in the per-protocol analysis set. The primary safety endpoint was the frequency of solicited local and systemic adverse events occurring within 7 days after each and any vaccination and were assessed in the safety analysis set (ie, all individuals who received at least one vaccination). This report includes safety and immunogenicity data through to month 12. This trial is ongoing but no longer recruiting participants, and is registered with Clinicaltrials.gov (NCT04801420). Between March 15, 2021, and Feb 24, 2022, 625 participants (321 [51%] female, 304 [49%] male) received one or more vaccinations and were included in the safety analysis set. Of these, 190 participants were included in the VLA15 M0-2-6 group, 187 were included in the VLA15 M0-6 group, and 208 were included in the placebo group; 40 additional VLA15 recipients could not be allocated to either VLA15 group because their vaccination schedules were non-compliant with both VLA15 groups due to missed or incorrect vaccinations; however, these individuals were included in safety analyses. OspA-specific ELISA IgG GMTs at month 7 in the overall population (aged 5–65 years) were significantly higher in the VLA15 M0-2-6 group (333·2 [95% CI 275·2–403·4; ST1] to 656·0 [560·2–768·2; ST2] units per mL) and VLA15 M0-6 group (197·3 [156·2–249·3; ST1] to 460·3 [370·6–571·8; ST2] units per mL) compared with the placebo group (21·9 [20·2–23·7; ST2] to 24·3 [22·1–26·7; ST6] units per mL; p<0·0001 for all comparisons); GMTs were also significantly higher in the VLA15 M0-2-6 group than in the VLA15 M0-6 group (all p<0·0001 except for ST2 [p=0·0010] and ST3 [p=0·011]). Among VLA15 recipients, GMTs were highest in children followed by adolescents and then adults. Solicited local adverse events after any vaccination occurred more frequently among VLA15 recipients (M0-2-6, 178 [94%; 95% CI 89–96] of 190; M0-6, 176 [94%; 90–97] of 187) than placebo recipients (71 [34%; 28–41] of 208; p<0·0001 for both comparisons); the same was true for solicited systemic adverse events (M0-2-6, 128 [67%; 95% CI 60–74] of 190, p=0·0015 vs placebo; M0-6, 128 [68%; 61–75] of 187, p=0·0007 vs placebo; placebo, 107 [51%; 45–58] of 208). Most solicited adverse events were mild or moderate in severity; none was grade 4. There were no significant differences in the frequencies of unsolicited adverse events, related unsolicited adverse events, unsolicited serious adverse events (serious adverse events), and adverse events of special interest across groups in the overall population. None of the severe unsolicited adverse events, serious adverse events, or adverse events of special interest were considered related to vaccination and no deaths occurred through to month 12 of the trial. These findings confirm previously observed safety and immunogenicity profiles of VLA15 in adults and extend them to children aged 5 years and older and adolescents. The greater immunogenicity of VLA15 among children and adolescents might translate to increased flexibility in the real-world clinical setting. Pfizer and Valneva.

•Streptococcus pneumoniae constitute a major global public health problem.•PnuBioVax, a novel multi-antigen protein vaccine against Streptococcus pneumoniae.•PnuBioVax is safe and immunogenic in healthy adult subjects: Phase 1 trial results. Pneumococcal vaccines, combining multiple protein antigens, provide an alternative approach to currently marketed vaccines and may provide broader protection against pneumococcal disease. This trial evaluated the safety and immunogenicity of a novel vaccine candidate PnuBioVax in healthy young adults. In a Phase 1 double-blind study, 36 subjects (18–40 years) were randomised to receive 3 doses of PnuBioVax, 28 days apart, at one of three dose levels (50, 200, 500 µg) or placebo. Safety assessments included rates of emergent adverse events (AEs), injection site and systemic reactions. Immunogenicity endpoints included antibody titre against PnuBioVax and selected pneumococcal antigens. In the placebo (n=9) and PnuBioVax (n=27) vaccinated subjects, there were 15 and 72, reported TEAEs, respectively. The majority of TEAEs were classified as common vaccine related AEs. There were no serious AEs. Common vaccine-related AEs occurred in 13 PnuBioVax (48%) and 2 placebo (22%) subjects and were all headaches (mild and moderate). Injection site reactions, mostly pain and tenderness (graded mild or moderate) were reported, in particular in the 200 µg and 500 µg PnuBioVax groups. There were no clinically significant changes in vital signs, ECG or blood chemistries. Subjects receiving the higher dose (200 and 500 μg) demonstrated a greater fold increase in IgG titre compared with the starting dose (50 μg) or the placebo group. The fold-increase was statistically significantly higher for 200 and 500µg PnuBioVax vs 50µg PnuBioVax and placebo at each timepoint post-immunisation. Most subjects receiving 200 and 500 µg PnuBioVax demonstrated a ≥2-fold increase in antibody against pneumolysin (Ply), Pneumococcal surface antigen (PsaA), PiaA (Pneumococcal iron acquisition), PspA (Pneumococcal surface protein A) and pilus proteins (RrgB and RrgA). All dose levels were considered safe and well tolerated. There was a statistically significant increase in anti-PnuBioVax IgG titres at the 200 and 500 µg dose levels compared to 50 µg and placebo. Trial registration number: NCT02572635https://www.clinicaltrials.gov.

GC1109, a novel recombinant protective antigen (PA) anthrax vaccine, has demonstrated promising immunogenicity in previous dose-finding trials. This study evaluated the immunogenicity and safety of four intramuscular doses of GC1109 in healthy adults. This randomized, double-blind, placebo-controlled phase 2 trial enrolled healthy volunteers aged 19 to 65 years. Participants were assigned in a 3: 1 ratio to receive either GC1109 (1.0 mL) or placebo at weeks 0, 4, 8, and 32. Immunogenicity was assessed using toxin neutralization antibody (TNA) titers and anti-PA IgG levels. The primary endpoint was the proportion of vaccine recipients achieving a TNA 50 % neutralization factor (NF50) ≥ 0.56 at week 36. Safety was evaluated through solicited and unsolicited adverse events (AEs). All participants in the GC1109 group achieved TNA NF50 ≥ 0.56 at week 36 (100 %, 95 % confidence interval: 97.6–100.0) and the predefined criterion for the primary endpoint was met. TNA and anti-PA IgG levels peaked at week 36 but declined thereafter. Pruritus was the only solicited AE significantly more frequent in the GC1109 group; serious AEs were rare and unrelated to vaccination. Four doses of GC1109 were immunogenic and generally well-tolerated. Further studies are needed to explore appropriate boosting strategies and evaluate safety in larger populations.

•A 4-antigen S. aureus vaccine (SA4Ag) targeting multiple virulence factors.•A Phase 1 study after finalizing manufacturing process prior to an efficacy study.•SA4Ag was well tolerated with a satisfactory safety profile in adults 18–<65years.•SA4Ag rapidly induced high level bacteria-killing antibodies in adults 18–<65years.•The postoperative protective effect of SA4Ag is being assessed in a Phase 2b trial. Staphylococcus aureus is a leading cause of healthcare-associated infections. No preventive vaccine is currently licensed. SA4Ag is an investigational 4-antigen S. aureus vaccine, composed of capsular polysaccharide conjugates of serotypes 5 and 8 (CP5 and CP8), recombinant surface protein clumping factor A (rmClfA), and recombinant manganese transporter protein C (rMntC). This Phase 1 study aimed to confirm the safety and immunogenicity of SA4Ag produced by the final manufacturing process before efficacy study initiation in a surgical population. Healthy adults (18–<65years) received one intramuscular SA4Ag injection. Serum functional antibodies were measured at baseline and Day 29 post-vaccination. An opsonophagocytic activity (OPA) assay measured the ability of vaccine-induced antibodies to CP5 and CP8 to kill S. aureus clinical isolates. For MntC and ClfA, antigen-specific immunogenicity was assessed via competitive Luminex® immunoassay (cLIA) and via fibrinogen-binding inhibition (FBI) assay for ClfA only. Reactogenicity and adverse event data were collected. One hundred participants were vaccinated. SA4Ag was well tolerated, with a satisfactory safety profile. On Day 29, OPA geometric mean titers (GMTs) were 45,738 (CP5, 95% CI: 38,078–54,940) and 42,652 (CP8, 95% CI: 32,792–55,477), consistent with 69.2- and 28.9-fold rises in bacteria-killing antibodies, respectively; cLIA GMTs were 2064.4 (MntC, 95% CI: 1518.2–2807.0) and 3081.4 (ClfA, 95% CI: 2422.2–3920.0), consistent with 19.6- and 12.3-fold rises, respectively. Similar to cLIA results, ClfA FBI titers rose 11.0-fold (GMT: 672.2, 95% CI: 499.8–904.2). The vast majority of participants achieved the pre-defined biologically relevant thresholds: CP5: 100%; CP8: 97.9%, ClfA: 87.8%; and MntC 96.9%. SA4Ag was safe, well tolerated, and rapidly induced high levels of bacteria-killing antibodies in healthy adults. A Phase 2B efficacy trial in adults (18–85years) undergoing elective spinal fusion is ongoing to assess SA4Ag’s ability to prevent postoperative invasive surgical site and bloodstream infections caused by S. aureus. Clinicaltrials.gov Identifier: NCT02364596.

Intradermal MVA85A, a candidate vaccine against tuberculosis, induces high amounts of Ag85A-specific CD4 T cells in adults who have already received the BCG vaccine, but aerosol delivery of this vaccine might offer immunological and logistical advantages. We did a phase 1 double-blind trial to compare the safety and immunogenicity of aerosol-administered and intradermally administered MVA85A In this phase 1, double-blind, proof-of-concept trial, 24 eligible BCG-vaccinated healthy UK adults were randomly allocated (1:1) by sequentially numbered, sealed, opaque envelopes into two groups: aerosol MVA85A and intradermal saline placebo or intradermal MVA85A and aerosol saline placebo. Participants, the bronchoscopist, and immunologists were masked to treatment assignment. The primary outcome was safety, assessed by the frequency and severity of vaccine-related local and systemic adverse events. The secondary outcome was immunogenicity assessed with laboratory markers of cell-mediated immunity in blood and bronchoalveolar lavage samples. Safety and immunogenicity were assessed for 24 weeks after vaccination. Immunogenicity to both insert Ag85A and vector modified vaccinia virus Ankara (MVA) was assessed by ex-vivo interferon-γ ELISpot and serum ELISAs. Since all participants were randomised and vaccinated according to protocol, our analyses were per protocol. This trial is registered with ClinicalTrials.gov, number NCT01497769. Both administration routes were well tolerated and immunogenic. Respiratory adverse events were rare and mild. Intradermal MVA85A was associated with expected mild local injection-site reactions. Systemic adverse events did not differ significantly between the two groups. Three participants in each group had no vaccine-related systemic adverse events; fatigue (11/24 [46%]) and headache (10/24 [42%]) were the most frequently reported symptoms. Ag85A-specific systemic responses were similar across groups. Ag85A-specific CD4 T cells were detected in bronchoalveolar lavage cells from both groups and responses were higher in the aerosol group than in the intradermal group. MVA-specific cellular responses were detected in both groups, whereas serum antibodies to MVA were only detectable after intradermal administration of the vaccine. Further clinical trials assessing the aerosol route of vaccine delivery are merited for tuberculosis and other respiratory pathogens. The Wellcome Trust and Oxford Radcliffe Hospitals Biomedical Research Centre.

•H4:IC31 vaccination was well tolerated with an acceptable safety profile.•H4:IC31 vaccination elicited persistent antigen-specific CD4+ T cell responses.•H4:IC31 triggered T cell expansion, IFNγ production and multifunctional Th1 cells.•Optimal antigen-adjuvant doses were 5, 15, or 50 μg of H4 plus 500 nmol of IC31. Novel vaccine strategies are required to provide protective immunity in tuberculosis (TB) and prevent development of active disease. We investigated the safety and immunogenicity of a novel TB vaccine candidate, H4:IC31 (AERAS-404) that is composed of a fusion protein of M. tuberculosis antigens Ag85B and TB10.4 combined with an IC31® adjuvant. BCG-vaccinated healthy subjects were immunized with various antigen (5, 15, 50, 150μg) and adjuvant (0, 100, 500nmol) doses of the H4:IC31 vaccine (n=106) or placebo (n=18) in two randomized, double-blind, placebo-controlled phase I studies conducted in a low TB endemic setting in Sweden and Finland. The subjects were followed for adverse events and CD4+ T cell responses. H4:IC31 vaccination was well tolerated with a safety profile consisting of mostly mild to moderate self-limited injection site pain, myalgia, arthralgia, fever and post-vaccination inflammatory reaction at the screening tuberculin skin test injection site. The H4:IC31 vaccine elicited antigen-specific CD4+ T cell proliferation and cytokine production that persisted 18weeks after the last vaccination. CD4+ T cell expansion, IFN-γ production and multifunctional CD4+ Th1 responses were most prominent after two doses of H4:IC31 containing 5, 15, or 50μg of H4 in combination with the 500nmol IC31 adjuvant dose. The novel TB vaccine candidate, H4:IC31, demonstrated an acceptable safety profile and was immunogenic, capable of triggering multifunctional CD4+ T cell responses in previously BCG-vaccinated healthy individuals. These dose-escalation trials provided evidence that the optimal antigen-adjuvant dose combinations are 5, 15, or 50μg of H4 and 500nmol of IC31. Trial registration: ClinicalTrials.gov, NCT02066428 and NCT02074956.

•SA4Ag is a novel multiantigen vaccine that targets S. aureus virulence factors.•A single dose of SA4Ag was well-tolerated in healthy adults aged 18–64years.•A robust functional immune response was elicited to each vaccine component.•Antibody rise was rapid and sustained after one dose of SA4Ag vaccine.•SA4Ag is a promising candidate vaccine to prevent invasive S. aureus infections. A prophylactic Staphylococcus aureus four-antigen vaccine (SA4Ag) is under development for prevention of invasive S. aureus disease. A preliminary S. aureus three-antigen vaccine (SA3Ag) was reformulated to include a novel manganese transporter protein (MntC or rP305A). This study describes the first-in-human dose-finding, safety, and immunogenicity results for SA4Ag. In this double-blind, sponsor-unblind, placebo-controlled, phase 1/2 study, 454 healthy adults aged 18–64years were randomised to receive a single dose of one of three formulations of SA4Ag with escalating dose levels of rP305A or placebo. Functional immune responses were measured using opsonophagocytic activity (OPA) killing and fibrinogen-binding inhibition (FBI) assays; antigen-specific immunogenicity was assessed using a four-plex competitive Luminex® immunoassay (cLIA). A high proportion of SA4Ag recipients met the pre-defined antibody thresholds for each antigen at Day 29. A substantial and dose-level dependent immune response was observed for rP305A, with up to 18-fold rises in cLIA titres at Day 29. Robust functional responses were demonstrated, with >80-fold and >20-fold rises in OPA assay titres at Day 29 using S. aureus strains expressing capsular polysaccharide serotypes 5 and 8, respectively. Durable antibody responses were observed through month 12, gradually waning from peak levels achieved by days 11–15. SA4Ag was well tolerated, and no vaccine-related serious adverse events were reported. Single-dose vaccination of SA4Ag in healthy adults aged 18–64years safely induced rapid and robust functional immune responses that were durable through month 12, supporting further development of this vaccine. Trial registration number: NCT01364571