Evaluation of the immune response to RTS,S/AS01 and RTS,S/AS02 adjuvanted vaccines : randomized, double-blind study in malaria-naïve adults

This phase II, randomized, double-blind study evaluated the immunogenicity of RTS, S vaccines containing Adjuvant System AS 01 or AS 02 as compared with non-adjuvanted RTS, S in healthy, malaria-naive adults (NCT00443131). Thirty-six subjects were randomized (1:1:1) to receive RTS, S/AS 01, RTS, S/AS 02, or RTS, S/saline at months 0, 1, and 2. Antibody responses to Plasmodium falciparum circumsporozoite (CS) and hepatitis B surface (HBs) antigens were assessed and cell-mediated immune responses evaluated by flow cytometry using intracellular cytokine staining on peripheral blood mononuclear cells. Anti-CS antibody avidity was also characterized. Safety and reactogenicity after each vaccine dose were monitored. One month after the third vaccine dose, RTS, S/AS 01 (160.3 EU/mL [95%CI: 114.1-225.4]) and RTS, S/AS 02 (77.4 EU/mL (95%CI: 47.3-126.7)) recipients had significantly higher anti-CS antibody geometric mean titers (GMTs) than recipients of RTS, S/saline (12.2 EU/mL (95%CI: 4.8-30.7); P < 0.0001 and P = 0.0011, respectively). The anti-CS antibody GMT was significantly higher with RTS, S/AS 01 than with RTS, S/AS 02 (P = 0.0135). Anti-CS antibody avidity was in the same range in all groups. CS- and HBs-specific CD4(+) T cell responses were greater for both RTS, S/AS groups than for the RTS, S/saline group. Reactogenicity was in general higher for RTS, S/AS compared with RTS, S/saline. Most grade 3 solicited adverse events (AEs) were of short duration and grade 3 solicited general AEs were infrequent in the 3 groups. No serious adverse events were reported. In conclusion, in comparison with non-adjuvanted RTS, S, both RTS, S/AS vaccines exhibited better CS-specific immune responses. The anti-CS antibody response was significantly higher with RTS, S/AS 01 than with RTS, S/AS 02. The adjuvanted vaccines had acceptable safety profiles

Detection of H1 swine influenza a virus antibodies in human serum samples by age group

Most H1 influenza A viruses (IAVs) of swine are derived from past human viruses. As human population immunity against these IAVs gradually decreases, the risk of reintroduction to humans increases. We examined 549 serum samples from persons 0-97 years of age collected in Belgium during 2017-2018 for hemagglutination inhibiting and virus neutralizing antibodies against 7 major H1 swine IAV (swIAV) clades and 3 human progenitor IAVs. Seroprevalence (titers >= 40) rates were >= 50% for classical swine and European human-like swIAVs, >= 24% for North American human-like delta 1a and Asian avian-like swIAVs, and <= 10% for North American human-like delta 1b and European avian-like swIAVs, but rates were age-dependent. Antibody titers against human-like swIAVs and supposed human precursor IAVs correlated with correlation coefficients of 0.30-0.86. Our serologic findings suggest that European avian-like, Glade 1C.2.1, and North American human-like delta 1b, Glade 16.2.2.2, H1 swIAVs pose the highest pandemic risk

Antibody persistence and booster responses to split-virion H5N1 avian influenza vaccine in young and elderly adults

Avian influenza continues to circulate and remains a global health threat not least because of the associated high mortality. In this study antibody persistence, booster vaccine response and cross-clade immune response between two influenza A(H5N1) vaccines were compared. Participants aged over 18-years who had previously been immunized with a clade 1, A/Vietnam vaccine were re-immunized at 6-months with 7.5 mu g of the homologous strain or at 22-months with a clade 2, alum-adjuvanted, A/Indonesia vaccine. Blood sampled at 6, 15 and 22-months after the primary course was used to assess antibody persistence. Antibody concentrations 6-months after primary immunisation with either A/Vietnam vaccine 30 mu g alum-adjuvanted vaccine or 7.5 mu g dose vaccine were lower than 21days after the primary course and waned further with time. Re-immunization with the clade 2, 30 mu g alum-adjuvanted vaccine confirmed cross-clade reactogenicity. Antibody crossreactivity between A(H5N1) clades suggests that in principle a prime-boost vaccination strategy may provide both early protection at the start of a pandemic and improved antibody responses to specific vaccination once available

Saccharomyces cerevisiae-derived HBsAg preparations differ in their attachment to monocytes, immune-suppressive potential, and T-cell immunogenicity

Expression of the hepatitis B virus S protein results in the formation of a lipoprotein particle, the hepatitis B surface antigen (HBsAg). Such particles, produced in Saccharomyces cerevisiae, bind to the cell surface of monocytes through interaction with the lipopolysaccharide binding protein and the lipopolysaccharide receptor, CD14. This attachment is suggested to depend on the presence of charged phospholipids in the particles. In addition, such particles interfere with the lipopolysaccharide and interleukin-2-induced activation of monocytes. In the present study, it is reported that of three Saccharomyces cerevisiae-derived HBsAg preparations, two have a reduced capacity to bind to monocytes. A correlation with a reduced potential to inhibit the lipopolysaccharide-induced activation of monocytes and an increased potential to stimulate HBsAg-specific T-cell proliferation is observed. Surprisingly, differences in phospholipid content that might explain these observations, were not detected. (C) 2003 Wiley-Liss, In

Impact of lipids and lipoproteins on hepatitis C virus infection and virus neutralization

Hepatitis C virus (HCV) infections represent a major global health problem. End-stage liver disease caused by chronic HCV infection is a major indication for liver transplantation. However, after transplantation the engrafted liver inevitably becomes infected by the circulating virus. Direct acting antivirals are not yet approved for use in liver transplant patients, and limited efficacy and severe side effects hamper the use of pegylated interferon combined with ribavirin in a post-transplant setting. Therefore, alternative therapeutic options need to be explored. Viral entry represents an attractive target for such therapeutic intervention. Understanding the mechanisms of viral entry is essential to define the viral and cellular factors involved. The HCV life cycle is dependent of and associated with lipoprotein physiology and the presence of lipoproteins has been correlated with altered antiviral efficacy of entry inhibitors. In this review, we summarise the current knowledge on how lipoprotein physiology influences the HCV life cycle. We focus especially on the influence of lipoproteins on antibodies that target HCV envelope proteins or antibodies that target the cellular receptors of the virus. This information can be particularly relevant for the prevention of HCV re-infection after liver transplantation

A monoclonal antibody-based immunoassay to measure the antibody response against the repeat region of the circumsporozoite protein of Plasmodium falciparum

Background: The malaria vaccine candidate RTS, S/AS01 (GSK Vaccines) induces high IgG concentration against the circumsporozoite protein (CSP) of Plasmodium falciparum. In human vaccine recipients circulating anti-CSP antibody concentrations are associated with protection against infection but appear not to be the correlate of protection. However, in a humanized mouse model of malaria infection prophylactic administration of a human monoclonal antibody (MAL1C), derived from a RTS, S/AS01-immunized volunteer, directed against the CSP repeat region, conveyed full protection in a dose-dependent manner suggesting that antibodies alone are able to prevent P. falciparum infection when present in sufficiently high concentrations. A competition ELISA was developed to measure the presence of MAL1C-like antibodies in polyclonal sera from RTS, S/AS01 vaccine recipients and study their possible contribution to protection against infection. Results: MAL1C-like antibodies present in polyclonal vaccine-induced sera were evaluated for their ability to compete with biotinylated monoclonal antibody MAL1C for binding sites on the capture antigen consisting of the recombinant protein encompassing 32 NANP repeats of CSP (R32LR). Serum samples were taken at different time points from participants in two RTS, S/AS01 vaccine studies (NCT01366534 and NCT01857869). Vaccine-induced protection status of the study participants was determined based on the outcome of experimental challenge with infected mosquito bites after vaccination. Optimal conditions were established to reliably detect MAL1C-like antibodies in polyclonal sera. Polyclonal anti-CSP antibodies and MAL1C-like antibody content were measured in 276 serum samples from RTS, S/AS01 vaccine recipients using the standard ELISA and MAL-1C competition ELISA, respectively. A strong correlation was observed between the results from these assays. However, no correlation was found between the results of either assay and protection against infection. Conclusions: The competition ELISA to measure MAL1C-like antibodies in polyclonal sera from RTS, S/AS01 vaccine recipients was robust and reliable but did not reveal the elusive correlate of protection

Phase I, randomized, observer-blind, placebo-controlled studies to evaluate the safety, reactogenicity and immunogenicity of an investigational non-typeable Haemophilus influenzae (NTHi) protein vaccine in adults

Background: Non-typeable Haemophilus influenzae (NTHi) is a major cause of various respiratory diseases. The development of an effective vaccine against NTHi mandates new approaches beyond conjugated vaccines as this opportunistic bacterium is non-encapsulated. Here we report on the safety, reactogenicity and immunogenicity of a multi-component investigational vaccine based on three conserved surface proteins from NTHi (proteins D [PD],E [PE] and Pilin A [PilA]) in two observer-blind phase I studies. Methods: In the first study (NCT01657526), 48 healthy 18-40 year-olds received two vaccine formulations (10 or 30 mu g of each antigen [PD and a fusion protein PE-PilA]) or saline placebo at months 0 and 2. In the second study (NCT01678677), 270 50-70 year-olds, current or former smokers, received eight vaccine formulations (10 or 30 mu g antigen/dose non-adjuvanted or adjuvanted with alum, AS01(E) or ASO4(c)) or saline placebo at months 0,2 and 6 (plain and alum-adjuvanted groups) and at months 0 and 2 (AS-adjuvanted groups). Solicited and unsolicited adverse events (AEs) were recorded for 7 and 30 days post-vaccination, respectively; potential immune-mediated diseases (pIMDs) and serious AEs (SAEs) throughout the studies. Humoral and antigen-specific T-cell immunity (in study 2 only) responses were assessed up to 12 months post-vaccination. Results: Observed reactogenicity was highest in the AS-adjuvanted groups but no safety concerns were identified with any of the NTHi vaccine formulations. One fatal SAE (cardiac arrest) not considered related to vaccination, and one pIMD (non-serious psoriasis) in the Placebo group, were reported post-dose 3 in Study 2. All formulations generated a robust antibody response while the AS01-adjuvanted formulations produced the highest humoral and cellular immune responses. Conclusion: This study confirms that the NTHi vaccine formulations had an acceptable reactogenicity and safety profile and were immunogenic in adults. These results justify further clinical development of this NTHi vaccine candidate

Production, characterization and in vitro testing of HBcAg-specific VHH intrabodies

Hepatitis B virus (HBV) infections represent a global health problem, since these account for 350 million chronic infections worldwide that result in 500 000-700 000 deaths each year. Control of viral replication and HBV-related disease and mortality are of utmost importance. Because the currently available antiviral therapies all have major limitations, new strategies to treat chronic HBV infection are eagerly awaited. Six single-domain antibodies (VHHs) targeting the core antigen of HBV (HBcAg) have been generated and three of these bound strongly to HBcAg of both subtype ayw and adw. These three VHHs were studied as intrabodies directed towards the nucleus or the cytoplasm of a hepatoma cell line that was co-transfected with HBV. A speckled staining of HBcAg was observed in the cytoplasm of cells transfected with nucleotropic VHH intrabodies. Moreover, an increased intracellular accumulation of hepatitis B e antigen (HBeAg) and a complete disappearance of intracellular HBcAg signal were observed with nuclear targeted HBcAg-specific VHHs. These results suggest that HBcAg-specific VHHs targeted to the nucleus affect HBcAg and HBeAg expression and trafficking in HBV-transfected hepatocytes