scholarly journals Phase 1 and Phase 2 Studies of Salmonella enterica Serovar Paratyphi A O-Specific Polysaccharide-Tetanus Toxoid Conjugates in Adults, Teenagers, and 2- to 4-Year-Old Children in Vietnam

2000 ◽  
Vol 68 (3) ◽  
pp. 1529-1534 ◽  
Author(s):  
Edward Y. Konadu ◽  
Feng-Ying C. Lin ◽  
Vô Anh Hó ◽  
Nguyen Thi Thanh Thuy ◽  
Phan Van Bay ◽  
...  
Keyword(s):  
Side Effects ◽  
Bactericidal Activity ◽  
Tetanus Toxoid ◽  
Salmonella Enterica ◽  
Phase 1 ◽  
Geometric Mean ◽  
Age Groups ◽  
Significant Rise ◽  
Phase 2 ◽  
Specific Polysaccharide

ABSTRACT Salmonella enterica serovar Paratyphi A O-specific polysaccharide (O-SP) was activated with 1-cyano-4-dimethylaminopyridinium tetrafluoroborate (CDAP) and bound to tetanus toxoid (TT) with adipic acid dihydrazide as a linker (SPA-TT1) or directly (SPA-TT2). In mice, these two conjugates elicited high levels of immunoglobulin G (IgG) anti-lipopolysaccharide (LPS) in serum with bactericidal activity (E. Konadu, J. Shiloach, D. A. Bryla, J. B. Robbins, and S. C. Szu, Infect. Immun. 64:2709–2715, 1996). The safety and immunogenicity of the two conjugates were then evaluated sequentially in Vietnamese adults, teenagers, and 2- to 4-year-old children. None of the vaccinees experienced significant side effects, and all had preexisting LPS antibodies. At 4 weeks after injection, there were significant increases of the geometric mean IgG and IgM anti-LPS levels in the adults and teenagers: both conjugates elicited a greater than fourfold rise in the IgG anti-LPS level in serum in ≥80% of the volunteers. SPA-TT2 elicited slightly higher, though not statistically significantly, levels of IgG anti-LPS than did SPA-TT1 in these age groups. Accordingly, only SPA-TT2 was evaluated in the 2- to 4-year-old children. On a random basis, one or two injections were administered 6 weeks apart to the children. No significant side effects were observed, and the levels of preexisting anti-LPS in serum were similar in children of all ages. A significant rise in the IgG anti-LPS titer was elicited by the first injection (P = 0.0001); a second injection did not elicit a booster response. Representative sera from all groups had bactericidal activity that could be adsorbed by S. enterica serovar Paratyphi A LPS.

scholarly journals Kinetics of the Natural, Humoral Immune Response to Salmonella enterica Serovar Typhi in Kathmandu, Nepal

2009 ◽  
Vol 16 (10) ◽  
pp. 1413-1419 ◽  
Author(s):  
Anoop S. Pulickal ◽  
Samir Gautam ◽  
Elizabeth A. Clutterbuck ◽  
Stephen Thorson ◽  
Buddha Basynat ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Salmonella Enterica ◽  
Capsular Polysaccharide ◽  
Geometric Mean ◽  
Public Health Problem ◽  
Major Public Health Problem ◽  
Natural Immunity ◽  
Humoral Immune ◽  
Bactericidal Antibody ◽  
Stratified Sample

ABSTRACT Typhoid fever is a major public health problem in developing countries, conservatively estimated to occur in 17 million cases and be responsible for 200,000 deaths annually. We investigated the acquisition of natural immunity to Salmonella enterica serovar Typhi in a region where typhoid is endemic by testing sera from an age-stratified sample of 210 healthy participants in Kathmandu, Nepal, for bactericidal activity toward S. Typhi and for anti-Vi capsular polysaccharide antibodies. Bactericidal titers in children were significantly lower than those in newborns and adults (P < 0.0001). Anti-S. Typhi bactericidal geometric mean titers were age dependent, increasing 10-fold during childhood. Anti-Vi polysaccharide antibody geometric mean concentrations were also lower in children than in adults. Data presented here indicate the possibility of a relationship between low levels of bactericidal activity toward S. Typhi in serum and susceptibility to disease, as observed for other polysaccharide-encapsulated bacteria. Bactericidal antibody may be a marker of protective immunity against S. Typhi.

scholarly journals Characterization of a Monoclonal Antibody Directed against Salmonella enterica Serovar Typhimurium and Serovar [4,5,12:i:−]

2009 ◽  
Vol 75 (5) ◽  
pp. 1345-1354 ◽  
Author(s):  
A. Rementeria ◽  
A. B. Vivanco ◽  
A. Ramirez ◽  
F. L. Hernando ◽  
J. Bikandi ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Western Blotting ◽  
Salmonella Enterica ◽  
Phase 1 ◽  
Enzyme Linked Immunosorbent Assay ◽  
Phase 2 ◽  
Serovar Typhimurium ◽  
Antigenic Complex ◽  
Dot Blotting

ABSTRACT Flagellar extracts of Salmonella enterica serovars expressing phase 2 H1 antigenic complex (H:1,2, H:1,5, H:1,6, and H:1,7) and a mutant flagellin obtained by site-directed mutagenesis of the fljB gene from serovar Typhimurium at codon 218, transforming threonine to alanine, expressed in Escherichia coli (fljB218 A ) were used to analyze the H1 antigenic complex. Cross-reactions were detected by Western blotting and dot blotting using commercial polyclonal antibodies against the different wild-type extracts and mutant FljB218A. Therefore, we produced a monoclonal antibody (MAb), 23D4, isotyped as immunoglobulin M, against H:1,2 S. enterica serovar Typhimurium flagellin. The mutant flagellin was not recognized by this MAb. When a large number of phase 1 and phase 2 flagellin antigens of different serovars were used to characterize the 23D4 MAb, only extracts of serovars Typhimurium and [4,5,12:i:−] reacted. The protein composition of phase 1 and phase 2 extracts and highly purified H:1,2 flagellin from serovar Typhimurium strain LT2 and extract of strain 286 (serovar [4,5,12:i:−]), which reacted with the MAb, was studied. Phase 2 flagellin (FljBH:1,2) was detected in phase 1 and phase 2 flagellar heat extracts of serovar Typhimurium and was the single protein identified in all spots of purified H:1,2 flagellin. FliC, FlgK, and other proteins were detected in some immunoreactive spots and in the flagellar extract of serovar [4,5,12:i:−]. Immunoelectron microscopy of complete bacteria with 23D4 showed MAb attachment at the base of flagella, although the MAb failed to recognize the filament of flagella. Nevertheless, the results obtained by the other immunological tests (enzyme-linked immunosorbent assay, Western blotting, and dot blotting) indicate a reaction against flagellins. The epitopes could also be shared by other proteins on spots where FljB is not present, such as aminopeptidase B, isocitrate lyase, InvE, EF-TuA, enolase, DnaK, and others. In conclusion, MAb 23D4 can be useful for detection and diagnostic purposes of S. enterica serovar Typhimurium and serovar [4,5,12:i:−] and could be also helpful for epitope characterization of flagellum-associated antigens.

scholarly journals Meningococcal Polysaccharide AO-Acetylation Levels Do Not Impact the Immunogenicity of the Quadrivalent Meningococcal Tetanus Toxoid Conjugate Vaccine: Results from a Randomized, Controlled Phase III Study of Healthy Adults Aged 18 to 25 Years

2013 ◽  
Vol 20 (10) ◽  
pp. 1499-1507 ◽  
Author(s):  
Socorro Lupisan ◽  
Kriengsak Limkittikul ◽  
Nestor Sosa ◽  
Pornthep Chanthavanich ◽  
Véronique Bianco ◽  
...  
Keyword(s):  
Conjugate Vaccine ◽  
Bactericidal Activity ◽  
Tetanus Toxoid ◽  
Geometric Mean ◽  
Phase Iii ◽  
Controlled Study ◽  
Rabbit Serum ◽  
Vaccine Response ◽  
Serum Bactericidal Activity ◽  
Phase Iii Study

ABSTRACTIn this study, we compared the immunogenicities of two lots of meningococcal ACWY-tetanus toxoid conjugate vaccine (MenACWY-TT) that differed in serogroup A polysaccharide (PS)O-acetylation levels and evaluated their immunogenicities and safety in comparison to a licensed ACWY polysaccharide vaccine (Men-PS). In this phase III, partially blinded, controlled study, 1,170 healthy subjects aged 18 to 25 years were randomized (1:1:1) to receive one dose of MenACWY-TT lot A (ACWY-A) (68%O-acetylation), MenACWY-TT lot B (ACWY-B) (92%O-acetylation), or Men-PS (82%O-acetylation). Immunogenicity was evaluated in terms of serum bactericidal activity using rabbit complement (i.e., rabbit serum bactericidal activity [rSBA]). Solicited symptoms, unsolicited adverse events (AEs), and serious AEs (SAEs) were recorded. The immunogenicities, in terms of rSBA geometric mean titers, were comparable for both lots of MenACWY-TT. The vaccine response rates across the serogroups were 79.1 to 97.0% in the two ACWY groups and 73.7 to 94.1% in the Men-PS group. All subjects achieved rSBA titers of ≥1:8 for all serogroups. All subjects in the two ACWY groups and 99.5 to 100% in the Men-PS group achieved rSBA titers of ≥1:128. Pain was the most common solicited local symptom and was reported more frequently in the ACWY group (53.9 to 54.7%) than in the Men-PS group (36.8%). The most common solicited general symptoms were fatigue and headache, which were reported by 28.6 to 30.3% and 26.9 to 31.0% of subjects, respectively. Two subjects reported SAEs; one SAE was considered to be related to vaccination (blighted ovum; ACWY-B group). The level of serogroup A PSO-acetylation did not affect vaccine immunogenicity. MenACWY-TT (lot A) was not inferior to Men-PS in terms of vaccine response and was well tolerated.

scholarly journals 16. A Randomized Phase 1 Study of a Novel Pneumococcal Conjugate Vaccine in Healthy Japanese Adults in the United States

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S30-S31
Author(s):  
David Fitz-Patrick ◽  
Mariano Young Jr. ◽  
Daniel Scott ◽  
Ingrid L Scully ◽  
Gary Baugher ◽  
...  
Keyword(s):  
United States ◽  
Conjugate Vaccine ◽  
Phase 1 ◽  
Geometric Mean ◽  
Age Groups ◽  
Unmet Need ◽  
The United States ◽  
Double Blind Study ◽  
Double Blind ◽  
Japanese Adults

Abstract Background Because of the number and variability of serotypes causing pneumococcal disease among different geographic regions, age groups, and environmental backgrounds, expanding serotype coverage with pneumococcal conjugate vaccines (PCVs) is a continued unmet need. Methods This phase 1, randomized, double-blind study included healthy Japanese adults aged 18–49 years residing in the United States. Subjects were randomized 1:1:1 to receive a single dose of a 20-valent PCV (containing 13-valent PCV [PCV13] serotypes plus 8, 10A, 11A, 12F, 15B, 22F, 33F), a novel pneumococcal polysaccharide conjugate vaccine with extended coverage, or PCV13 (control). Safety was the primary endpoint and included reactogenicity events occurring ≤ 14 days after vaccination, adverse events (AEs) ≤ 1 month after vaccination, and serious AEs (SAEs) ≤ 6 months after vaccination. The secondary endpoint was pneumococcal serotype-specific immunogenicity as determined by opsonophagocytic activity (OPA) titers on sera collected before and 1 month after vaccination. Results Overall, 35 subjects received PCV20 and 35 subjects received PCV13. One subject withdrew before the 1-month follow-up. Local reactions and systemic events across groups were generally mild or moderate (Figure 1). Two vaccine-related AEs occurred (injection site erythema and swelling in the PCV20 group); no severe AEs, SAEs, or safety-related withdrawals were reported. OPA geometric mean titers increased for all 20 serotypes in the PCV20 group and all 13 serotypes in the PCV13 group 1 month after vaccination; corresponding OPA geometric mean fold rises from baseline to 1 month after vaccination are reported (Figure 2; Figure 3). Figure 1 Figure 2 Figure 3 Conclusion PCV20 was well tolerated and induced serotype-specific functional OPA immune responses that are anticipated to be associated with protection in Japanese adults. ClinicalTrials.gov: NCT03642847. Funding: Pfizer Inc. Disclosures David Fitz-Patrick, MD, Pfizer Inc (Grant/Research Support) Mariano Young Jr., MD, Pfizer Inc (Employee, Shareholder) Daniel Scott, MD, Pfizer (Employee, Shareholder) Ingrid L. Scully, PhD, Pfizer Inc (Employee, Shareholder) Gary Baugher, PharmD, Pfizer Inc (Employee, Shareholder) Yahong Peng, PhD, Pfizer (Employee, Shareholder) Kathrin U. Jansen, PhD, Pfizer (Employee, Shareholder) William C. Gruber, MD, Pfizer (Employee, Shareholder) Wendy Watson, MD, Pfizer (Employee, Shareholder)

scholarly journals The incidence and significance of Phase 1 complement-fixing antibody in Q fever

1962 ◽  
Vol 60 (3) ◽  
pp. 359-364 ◽  
Author(s):  
O. W. Powell ◽  
N. D. Stallman
Keyword(s):  
Persistent Infection ◽  
Q Fever ◽  
Phase 1 ◽  
Age Groups ◽  
Acute Illness ◽  
Older Age ◽  
Consecutive Series ◽  
Phase 2 ◽  
Senior Lecturer

1. An attempt has been made to follow up a consecutive series of seventy-two patients for the presence of Phase 1 C.F. antibody approximately 2 years or more after the acute illness. Fifty-one of the series were tested.2. Fifteen of the fifty-one patients had detectable amounts of antibody, generally in low titre.3. The presence of Phase 1 antibody correlated well, in older age-groups, with the duration of convalescence following the acute illness. There was no correlation with the duration of fever.4. All cases with Phase 1 antibody also had Phase 2 antibody, usually in slightly higher titre. In no case in which Phase 2 antibody was absent or present in low titre was Phase 1 antibody found.5. It is suggested that the presence of Phase 1 C.F. antibody is an indication of past persistent infection. It cannot necessarily be concluded that it is an indication of present persisting infection.We wish to thank Dr H. Silverstone, Senior Lecturer in Medical Statistics, University of Queensland, for statistical advice.

Clinical pharmacologic considerations for the phase II/III dose/regimen of the investigational Aurora A kinase (AAK) inhibitor MLN8237 (alisertib): Pharmacokinetics (PK), pharmacodynamics (PD), and exposure-safety relationships.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2597-2597
Author(s):  
Karthik Venkatakrishnan ◽  
Xiaofei Zhou ◽  
Jeffrey Ecsedy ◽  
Hadi Danaee ◽  
Hugh Xiao ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Body Size ◽  
Tumor Cells ◽  
Dose Regimen ◽  
Phase 1 ◽  
Geometric Mean ◽  
Dose Range ◽  
Systemic Exposure ◽  
Phase 2 ◽  
Pharmacologically Active

2597 Background: MLN8237, an oral selective AAK inhibitor, is primarily metabolized by multiple glucuronidation enzymes including the polymorphic UGT1A1. Phase 1 studies included comprehensive PK and PD sampling. We report integrated PK, PD, and PK-safety analyses in support of dose/regimen selection for phase 2/3 studies. Methods: Phase 1 studies in adults with advanced cancers evaluated dosing on d 1-7 in 21-d cycles or d 1-21 in 35-d cycles. Data from 294 patients in 4 phase 1 and 2 phase 2 studies contributed to population PK modeling. PD endpoints included mitotic index (MI) in skin and chromosome alignment and spindle bipolarity (CA/SB) in mitotic tumor cells. Logistic regression analyses evaluated relationships between MLN8237 PK parameters and DLTs (N=86) or CNS adverse events (AEs; n=134) in 2 phase 1 studies. Results: MLN8237 displayed dose-linear PK (5-200 mg/d), described by a 2-compartment model with first order absorption. Covariate analyses did not reveal significant effects of age, body size, sex, UGT1A1 genotype, or creatinine clearance (≥30 mL/min). Exposure-related increases in skin MI and decreases in CA/SB in tumor mitotic cells confirmed AAK inhibition by MLN8237. At the MTD of 50 mg BID (d 1-7 dosing) geometric mean steady-state exposures (48,200 nM.hr) were comparable to those associated with ≥50% CA/SB reductions in mitotic tumor cells (57,300 nM.hr). Exposures at the 21-d MTD (QD dosing) were lower, favoring 50 mg BID (d 1-7 dosing) for further development. At 50 mg BID (d 1-7 dosing) logistic regression relating MLN8237 AUC to DLT rate estimated a DLT probability of 8% (95% CI 3-20%). Similar analyses identified Cmax rather than AUC as the predictor of CNS AEs, supporting BID dosing in adults to reduce peak concentrations while preserving total systemic exposure. Conclusions: MLN8237 exhibits dose-linear PK independent of age, body size, mild or moderate renal impairment, or UGT1A1*28 polymorphism. Exposures achieved at or near 50 mg BID are expected to result in tumor AAK inhibition, supporting a pharmacologically active dose range for future clinical development.

scholarly journals Understanding side effects of therapy for myasthenia gravis and their impact on daily life

BMC Neurology ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Elizabeth Dansie Bacci ◽  
Karin S. Coyne ◽  
Jiat-Ling Poon ◽  
Linda Harris ◽  
Audra N. Boscoe
Keyword(s):  
Side Effects ◽  
Myasthenia Gravis ◽  
Daily Life ◽  
Phase 1 ◽  
Phase 2 ◽  
Related Quality ◽  
Health Related ◽  
Current Therapies ◽  
Group Concept ◽  
Two Phases

Abstract Background Myasthenia gravis is a chronic, autoimmune, neuromuscular junction disorder characterized by skeletal muscle weakness. Current therapies for myasthenia gravis are associated with significant side effects. The objective of this study was to characterize the side effects, and associated health-related quality of life and treatment impacts, of traditional myasthenia gravis treatments. Methods This study had two phases; a Phase 1 interview and a 2-part web-based survey in Phase 2 that included brainstorming (Step 1) and rating (Step 2) exercises using group concept mapping. In Phase 1, all 14 participants reported experiencing side effects from myasthenia gravis treatments which had significant impacts on daily life. In Phase 2, 246 participants contributed to Step 1; 158 returned for Step 2. Results The brainstorming exercise produced 874 statements about side effects and their impact, which were reduced to 35 side effects and 23 impact-on-daily life statements. When rating these statements on severity, frequency, and tolerability, blood clots, infections/decreased immunity, weight gain, and diarrhea were the least tolerable and most severely rated. The most frequent and severe impacts were sleep interference and reduced physical and social activities. Conclusions Based on these findings, there appears to be a need for better and more tolerable treatments for myasthenia gravis patients.

scholarly journals Coadministration of Atazanavir-Ritonavir and Zinc Sulfate: Impact on Hyperbilirubinemia and Pharmacokinetics

2013 ◽  
Vol 57 (8) ◽  
pp. 3640-3644 ◽  
Author(s):  
Graeme Moyle ◽  
Laura Else ◽  
Akil Jackson ◽  
David Back ◽  
Manisha H. Yapa ◽  
...  
Keyword(s):  
Zinc Sulfate ◽  
Total Bilirubin ◽  
Phase 1 ◽  
Geometric Mean ◽  
Total Bilirubin Level ◽  
Unconjugated Bilirubin ◽  
Virologic Suppression ◽  
Phase 2 ◽  
Phase 3 ◽  
Unconjugated Hyperbilirubinemia

ABSTRACTAtazanavir (ATV) causes an elevation of unconjugated hyperbilirubinemia (HBR) as a result of UDP glucuronyltransferase (UGT) 1A1 inhibition. Zinc sulfate (ZnSO4) reduces unconjugated hyperbilirubinemia in individuals with Gilbert's syndrome. We assessed the changes in total, conjugated, and unconjugated bilirubin and the effect on ATV pharmacokinetics (PK) after single and 14-day dosing of ZnSO4. HIV patients, stable on ATV/ritonavir (ATV/r)-containing regimens with a total bilirubin level of >25mmol/liter received 125 mg daily of ZnSO4as Solvazinc tablets for 14 days. ATV/r and bilirubin concentrations were measured pre-ATV/r dose and 2, 4, 6, 8, and 24 h post-ATV/r dose; before ZnSO4initiation (phase 1), after a single dose (phase 2) and after 14 days (phase 3). Changes in bilirubin and ATV/r concentrations in the absence or presence of ZnSO4were evaluated by geometric mean ratios (GMRs) and 90% confidence intervals (CIs; we used phase 1 as a reference). Sixteen male patients completed the study maintaining virologic suppression; ZnSO4was well tolerated. Statistically significant declines in total bilirubinCmaxand AUC0–24of 16 and 17% were seen in phase2 and 20% in phase 3. Although there were no significant changes in conjugated bilirubin, unconjugated bilirubinCmaxand AUC0–24of were lower (17 and 19%, phase 2; 20 and 23% during phase 3). The ATV GMRs (90% CI) forCtrough,Cmax, and AUC0–24were 0.74 (0.62 to 0.89), 0.82 (0.70 to 0.97), and 0.78 (0.70 to 0.88). Intake of ZnSO4decreases total and unconjugated bilirubin and causes modest declines in ATV exposure. ZnSO4supplementation may be useful in management of ATV-related HBR in selected patients.

scholarly journals Targeted Secure Messages to Facilitate Access to Tobacco Treatment Counseling for Veterans: Feasibility Study (Preprint)

2017 ◽  
Author(s):  
Shaun Shahani ◽  
Pearl Korenblit ◽  
Pauline Thomas ◽  
Marian R Passannante ◽  
Richard Carr ◽  
...  
Keyword(s):  
Phase 1 ◽  
Age Groups ◽  
Response Rates ◽  
Phase 2 ◽  
Secure Messaging ◽  
Tobacco Treatment ◽  
Two Samples ◽  
Secure Email ◽  
Two Phases ◽  
And Gender

BACKGROUND Studies show that combining nicotine replacement therapy (NRT) with tobacco treatment counseling is most effective for smoking cessation. However, tobacco treatment counseling has been underutilized across the nation. A secure email message sent to patients already taking NRT was hypothesized to increase the utilization of tobacco treatment counseling among Veterans in New Jersey. Secure messaging for communication between patients and providers was implemented through a web-based password-protected, secure messaging account, where Veterans get notified through their personal email when they have a message awaiting them. OBJECTIVE The main objective of this project was to determine if there was a significant increase in adoption of tobacco treatment counseling among Veterans who received a secure message describing the options for tobacco treatment counseling available to them. Secondary objectives were to demographically characterize Veterans who were and were not enrolled in secure messaging, as well as those who opened or did not open a message. Finally, because the language and content of the messages were changed across project phases, this project also sought to determine (by analysis of response rates) the type of language that was most effective at eliciting a response. METHODS Over two phases, messages were sent to two samples of Veterans prescribed NRT within the prior 90 days of each phase. In phase 1, one message was sent in December 2015 (message 1). In phase 2, one message was sent in July 2016 (message 2) and the same message (message 3) was resent in August 2016 to persons who did not open message 2. Messages 2 and 3 were more directive than message 1. Response rates to message 1 versus message 2 were compared. A logistic regression analysis determined effect of age and gender on enrollment in secure messaging across both phases. The effectiveness of each phase at increasing tobacco treatment counseling was analyzed using a McNemar test. RESULTS Message 2, sent to 423 Veterans, had a significantly higher response rate than message 1, sent to 348 Veterans (18%, 17/93 vs 8%, 6/78, P=.04). Phase 2 (ie, messages 2 and 3) significantly increased utilization of tobacco treatment counseling (net increase of six tobacco treatment counseling adopters, P=.04), whereas phase 1 (ie, message 1) did not (net increase of two tobacco treatment counseling adopters, P=.48). Women (odds ratio [OR] 1.6, 95% CI 1.1-2.3) and those aged 30 to 49 years (compared to other age groups) were more likely to be enrolled in secure messaging. Gender and age were not significant predictors of opening or replying to either message. CONCLUSIONS Although the effect was small, secure messaging was a useful modality to increase tobacco treatment counseling. Directive content with a follow-up message appeared useful. Female Veterans and/or Veterans aged between 30 and 49 years are more likely to use secure messaging.

scholarly journals Different dose regimens of a SARS-CoV-2 recombinant spike protein vaccine (NVX-CoV2373) in younger and older adults: A phase 2 randomized placebo-controlled trial

PLoS Medicine ◽  
2021 ◽  
Vol 18 (10) ◽  
pp. e1003769
Author(s):  
Neil Formica ◽  
Raburn Mallory ◽  
Gary Albert ◽  
Michelle Robinson ◽  
Joyce S. Plested ◽  
...  
Keyword(s):  
Dose Regimen ◽  
Phase 1 ◽  
Late Phase ◽  
Age Groups ◽  
Neutralizing Antibody ◽  
Spike Protein ◽  
Wild Type Virus ◽  
Phase 2 ◽  
Type Virus ◽  
Wild Type

Background NVX-CoV2373 is a recombinant severe acute respiratory coronavirus 2 (rSARS-CoV-2) nanoparticle vaccine composed of trimeric full-length SARS-CoV-2 spike glycoproteins and Matrix-M1 adjuvant. Methods and findings The phase 2 component of our randomized, placebo-controlled, phase 1 to 2 trial was designed to identify which dosing regimen of NVX-CoV2373 should move forward into late-phase studies and was based on immunogenicity and safety data through Day 35 (14 days after the second dose). The trial was conducted at 9 sites in Australia and 8 sites in the United States. Participants in 2 age groups (aged 18 to 59 and 60 to 84 years) were randomly assigned to receive either 1 or 2 intramuscular doses of 5-μg or 25-μg NVX-CoV2373 or placebo, 21 days apart. Primary endpoints were immunoglobulin G (IgG) anti-spike protein response, 7-day solicited reactogenicity, and unsolicited adverse events. A key secondary endpoint was wild-type virus neutralizing antibody response. After enrollment, 1,288 participants were randomly assigned to 1 of 4 vaccine groups or placebo, with 1,283 participants administered at least 1 study treatment. Of these, 45% were older participants 60 to 84 years. Reactogenicity was predominantly mild to moderate in severity and of short duration (median <3 days) after first and second vaccination with NVX-CoV2373, with higher frequencies and intensity after second vaccination and with the higher dose. Reactogenicity occurred less frequently and was of lower intensity in older participants. Both 2-dose regimens of 5-μg and 25-μg NVX-CoV2373 induced robust immune responses in younger and older participants. For the 2-dose regimen of 5 μg, geometric mean titers (GMTs) for IgG anti-spike protein were 65,019 (95% confidence interval (CI) 55,485 to 76,192) and 28,137 (95% CI 21,617 to 36,623) EU/mL and for wild-type virus neutralizing antibody (with an inhibitory concentration of 50%—MN50%) were 2,201 (95% CI 1,343 to 3,608) and 981 (95% CI 560 to 1,717) titers for younger and older participants, respectively, with seroconversion rates of 100% in both age groups. Neutralizing antibody responses exceeded those seen in a panel of convalescent sera for both age groups. Study limitations include the relatively short duration of safety follow-up to date and current lack of immune persistence data beyond the primary vaccination regimen time point assessments, but these data will accumulate over time. Conclusions The study confirmed the phase 1 findings that the 2-dose regimen of 5-μg NVX-CoV2373 is highly immunogenic and well tolerated in younger adults. In addition, in older adults, the 2-dose regimen of 5 μg was also well tolerated and showed sufficient immunogenicity to support its use in late-phase efficacy studies. Trial registration ClinicalTrials.gov NCT04368988.

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