Immunogenicity Of Different Formulations Research Articles

121. A Respiratory Syncytial Virus Prefusion F Protein (RSVPreF3) Candidate Vaccine Administered in Older Adults in a Phase I/II Randomized Clinical Trial Is Immunogenic

BackgroundRSV causes significant disease burden in older adults, since reinfections are common and may lead to severe disease presentations while only supportive treatment is available. We present immunogenicity of different formulations of an investigational vaccine (RSVPreF3) in young and older adults.MethodsThis is a phase I/II, placebo-controlled, multi-country trial (NCT03814590). Healthy adults aged 18–40 years were randomized 1:1:1:1 to receive 2 doses of either Low-, Medium- or High-dose of RSVPreF3 non-adjuvanted vaccine or placebo, 2 months apart. Following favorable safety outcomes, adults aged 60–80 years were randomized 1:1:1:1:1:1:1:1:1:1 in a 2-step staggered manner to receive 1 of the 9 RSV vaccine formulations containing Low-, Medium- or High-dose of RSVPreF3, non-adjuvanted or adjuvanted with AS01E or AS01B, or placebo (same schedule). Humoral and cellular-mediated immune responses are assessed before and after each dose; results up to 1 month post-dose 1 are shown here.ResultsOf 48 adults aged 18–40 years and 1005 aged 60–80 years included in the exposed set, 42 and 933, respectively, were part of per-protocol set at 1 month post-dose 1. RSVPreF3 IgG geometric mean antibody concentrations were 8.4–13.5 and 7.2–12.8 fold-higher at 1 month post-dose 1 vs baseline in the 18–40- and 60–80-year-old vaccinees, respectively (Fig 1A). RSV-A neutralization activity significantly increased in all RSV vaccinees, geometric mean antibody titers being 7.5–13.7 and 5.6–9.9 fold-higher in 18–40- and 60–80-year-olds, respectively, at 1 month post-dose 1 vs baseline (Fig 1B). Geometric mean ratios of the fold increase between RSVPreF3 IgG antibody concentrations and RSV-A neutralizing antibody titers ranged between 0.9–1.1 in 18–40-year-old and 1.3–1.5 in 60–80-year-old vaccinees. A robust RSVPreF3-specific CD4+ T-cell response was elicited at 1 month post-dose 1 vs baseline in both 18–40- and 60–80-year-olds (Fig 2).Figure 1. RSVPreF3 IgG geometric mean antibody concentrations (GMCs, enzyme-linked immunosorbent assay, panel A), RSV-A neutralizing geometric mean antibody titers (GMTs, neutralization assay, panel B) Figure 2. RSVPreF3-specific CD4+ T-cells identified as expressing ≥2 markers among IL2, CD40L, TNF-□, IFN-□ (intracellular cytokine staining assay) ConclusionOne dose of RSVPreF3 candidate vaccine boosted humoral and cellular immune responses in all vaccinees. In older adults, higher humoral response, mostly neutralizing, was observed with increased RSVPreF3 antigen dosage and a tendency of higher cellular response was observed after adjuvanted formulations.FundingGlaxoSmithKline Biologicals SADisclosuresJavier Ruiz Guiñazú, MD MSc, GSK group of companies (Employee, Shareholder) Jelena Tica, PhD, GSK group of companies (Employee, Shareholder) Charles P. Andrews, MD, GSK group of companies (Scientific Research Study Investigator) Charles Fogarty, MD, GSK group of companies (Grant/Research Support) Edward Kerwin, MD, Amphastar (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)AstraZeneca (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Boehringer Ingelheim (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Chiesi (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Cipla (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)GSK group of companies (Employee, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Mylan (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Novartis (Employee, Advisor or Review Panel member, Research Grant or Support, Speaker’s Bureau)other around 40 pharmaceutical companies (Other Financial or Material Support, conducted multicenter clinical research trials)Pearl (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Sunovion (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Theravance (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau) Isabel Leroux-Roels, MD PhD, GSK group of companies (Scientific Research Study Investigator) Corinne Vandermeulen, MD PhD, GSK group of companies (Other Financial or Material Support, My university only received Grant/Research Support) Marie-Pierre David, MSc, GSK group of companies (Employee, Shareholder) Nancy Dezutter, PhD, PharmD, RPh, GSK group of companies (Employee, Shareholder) Nathalie De Schrevel, PhD, GSK group of companies (Employee) Laurence Fissette, MSc, GSK group of companies (Employee) Narcisa Mesaros, MD, MSc, GSK group of companies (Employee)

Safety and Immunogenicity of Different Formulations of the Takeda Norovirus Vaccine Candidate in Healthy Adults: A Randomized, Controlled, Double-Blind Clinical Trial

Safety and Immunogenicity of Different Formulations of the Takeda Norovirus Vaccine Candidate in Healthy Adults: A Randomized, Controlled, Double-Blind Clinical Trial

Safety and immunogenicity of three different formulations of an adjuvanted varicella-zoster virus subunit candidate vaccine in older adults: A phase II, randomized, controlled study

BackgroundThis study investigated the safety and immunogenicity of different formulations and schedules of a candidate subunit herpes zoster vaccine containing varicella-zoster virus glycoprotein E (gE) with or without the adjuvant system AS01B. MethodsIn this phase II, single-blind, randomized, controlled study, adults aged ≥60years (N=714) received one dose of 100μggE/AS01B, two doses, two months apart, of 25, 50, or 100μggE/AS01B, or two doses of unadjuvanted 100μggE/saline. Frequencies of CD4+ T cells expressing ≥2 activation markers following induction with gE were measured by intracellular cytokine staining and serum anti-gE antibody concentrations by ELISA. ResultsFrequencies of gE-specific CD4+ T cells were >3-fold higher after two doses of all gE/AS01B formulations than after one dose of 100μggE/AS01B or two doses of 100μggE/saline. Frequencies were comparable after two doses of 25, 50, or 100μggE/AS01B. Serum anti-gE antibody concentrations were comparable after two doses of 50 or 100μggE/AS01B and higher than in the other groups. Immune responses persisted for at least 36 months. Reactogenicities of all gE/AS01B formulations were similar but greater than with gE/saline. ConclusionsThe three formulations of gE/AS01B were immunogenic and well tolerated in adults aged ≥60years. Two vaccinations with gE/AS01B induced higher immune responses than one and the dose of gE impacted humoral but not cellular immune responses (NCT00434577).

A Randomized, Controlled Dose-Finding Phase II Study of the M72/AS01 Candidate Tuberculosis Vaccine in Healthy PPD-Positive Adults

PurposeIn this dose-finding Phase II study (NCT00621322), we evaluated the safety and immunogenicity of different formulations of the candidate tuberculosis vaccine containing the M72 antigen (10/20/40 μg doses) and the liposome-based AS01 Adjuvant System. We aimed to select the lowest-dose combination of M72 and AS01 that was clinically well tolerated with immunogenicity comparable to that of the previously tested M72/AS01B (40 μg) candidate vaccine.MethodsHealthy PPD-positive (induration 3–10 mm) adults (18–45 years) in The Philippines were randomized (4:4:4:4:1:1) to receive 2 injections, 1 month apart, of M72/AS01B (40 μg), M72/AS01E (10 μg), M72/AS01E (20 μg), M72/AS02D (10 μg), M72/Saline (40 μg) or AS01B alone, and were followed up for 6 months. AS01E and AS02D contain half the quantities of the immunostimulants present in AS01B. AS02D is an oil-in-water emulsion. Vaccine selection was based on the CD4+ T-cell responses at 1 month post vaccination.ResultsAll formulations had a clinically acceptable safety profile with no vaccine-related serious adverse events reported. Two vaccinations of each adjuvanted M72 vaccine induced M72-specific CD4+ T-cell and humoral responses persisting at 6 months post vaccination. No responses were observed with AS01B alone. One month post second vaccination, CD4+ T-cell responses induced by each of the three M72/AS01 vaccine formulations were of comparable magnitudes, and all were significantly higher than those induced by M72/AS02D (10 μg) and M72/Saline.ConclusionsThe formulation with the lowest antigen and adjuvant dose, M72/AS01E (10 μg), fulfilled our pre-defined selection criteria and has been selected for further clinical development.

Anti-interferon antibodies in multiple sclerosis. Molecular basis and their impact on clinical efficacy.

Low levels of naturally-occurring, high-affinity antibodies directed against cytokines can be found in the circulation of individuals who have never been exposed to exogenously-supplied cytokines. These antibodies are thought to play a regulatory role in the intensity and duration of immune response. Interferon (IFN) beta has been shown to attenuate both relapsing-remitting multiple sclerosis (MS) and secondary progressive MS in several well-powered, randomized, controlled clinical trials. IFN therapy can induce the production of anti-IFN neutralizing antibodies (NAb), usually in the second 6 months of treatment, in 3 to 45% of treated patients. This variation in the proportion of NAb-positive patients is probably due to the immunogenicity of different formulations of IFN beta, as well as the assay used, which are not currently standardized. The occurrence of NAb appears to be directly correlated with the dose of therapeutic IFN administered, up to a certain dose threshold. If the dose is increased beyond this threshold, the levels of NAb decrease. The biological significance of anti-IFN NAb is not yet known, nor has it been proven conclusively that they affect the clinical response to IFN beta therapy. The presence of NAb is therefore not an indication that treatment should be changed. Indeed, any treatment decision should be based only on the clinical response to therapy.

Bioactive fragment of human interleukin-1beta (163-171) modulates the immune response to synthetic peptides of RESA of Plasmodium falciparum.

In this study a bioactive fragment, residues 163-171 of human interleukin-1beta (hu IL-1beta), that mimics the functions of the whole IL-1 molecule was chemically linked to two peptide sequences of the ring erythrocyte surface antigen (RESA), an asexual blood stage antigen of Plasmodium falciparum. The immunogenicity of different formulations was studied in different haplotypes of inbred mice. The peptide-IL-1beta conjugates delivered in liposomes showed the maximal antibody production. Antigen entrapped in liposomes at a dose of 5 microg showed antibody levels comparable to that of peptide conjugate in alum. The IgG subclass profile with different RESA peptides and its conjugates at various doses in liposomes induced predominantly IgG2a/2b isotypes while alum-delivered formulations showed both IgG1 and IgG2a/2b isotypes. In vitro studies of merozoite reinvasion showed varying degree (50-85%) of inhibition, maximum being with the peptide conjugates in liposomes (80-87%). Thus, this approach suggests that linking of hu IL-1beta is instrumental in augmenting the immune response against otherwise poorly immunogenic synthetic peptides.

Influence of immunoadjuvants and a promiscous T-cell determinant on the immunogenicity of RESA peptide antigen of P. falciparum

Synthetic peptide antigens representing the repeat sequences of malarial antigens showed poor immunogenicity and protection in clinical trials. In the present study, RESA, an asexual blood stage antigen, containing (EENVEHDA) 2 and (DDEHVEEPTVA) 2 sequences were chemically linked to a promiscous T-cell determinant (CS.T3) of the circumsporozoite protein of P.falciparum. The synthetic constructs either alone or coentrapped with immunoadjuvants (nor muramyl dipeptide\\lauroyl tetrapeptide) were admini- stered in liposomes to mice of varying genetic background and the immunogenicity of different formulations were compared under identical experimental conditions. The RESA peptide formulations containing the T-cell determinant and the adjuvants generated high titre and affinity antibodies in all the strains, as compared to peptide(s) alone. The booster immunization induced a strong anamnestic response in each group. Though the major IgG isotype is of IgG 1 and IgG 2b interestingly, formulations containing CS.T3 have a higher proportion of cytophilic IgG 2b isotype. There was a significant fall in the levels of IgG 2b isotype while IgG 1 levels were maintained same in the third bleed (day 60, without booster immunization). The mixed peptide group preparation containing the adjuvant is found to be a better immunogen than that of respective peptides itself. The in vitro merozoite reinvasion inhibition assay showed 76–96% inhibition with the formulations containing RESA peptide(s)-CS.T3 and the adjuvant, while with peptides alone the inhibition was 50–56%. This study highlights the importance of an alternative approach for developing peptide based immunogen against malaria.