NPJ Vaccines最新文献

Plasmodium vivax is the most widespread of the different Plasmodium species able to infect humans and is responsible for most malaria cases outside Africa. An effective, strain-transcending vaccine that alleviates or suppresses erythrocyte invasion would be a game-changer in eliminating vivax malaria. Recently, the binding of P. vivax Reticulocyte Binding Protein 2b (PvRBP2b) to human Transferrin receptor (TfR1) has been described as essential for reticulocyte invasion, making this parasite protein an appealing vaccine candidate. Here, using P. vivax Cambodian clinical isolates in robust ex vivo invasion assays, we show that anti-PvRBP2b polyclonal and monoclonal antibodies that inhibit binding of PvRBP2b to TfR1 do not block P. vivax invasion into reticulocytes even at high concentrations. Anti-TfR1 antibodies do not inhibit P. vivax invasion either. Combinations at high concentrations of human monoclonal antibodies targeting different PvRBP2b epitopes do not inhibit invasion. Combinations of anti-PvRBP2b with anti-PvDBP do not enhance invasion inhibition caused by anti-PvDBP alone. We also show that the invasion of Cambodian P. vivax is trypsin-resistant while TfR1 is trypsin-sensitive, and we demonstrate that TfR1 is not recycled following trypsin treatment. We determined the PvRBP2b sequence of all isolates used in the invasion assays and analyzed polymorphism within epitopes recognized by anti-PvRBP2b antibodies. We show that polymorphism does not explain the absence of neutralization. Anti-PvRBP2b polyclonal antibodies recognized all four isolates tested in immunofluorescence assays while not inhibiting P. vivax invasion. Overall, our results demonstrate that PvRBP2b binding to TfR1 is not essential for invasion into reticulocytes of P. vivax Cambodian strains questioning the relevance of PvRBP2b as vaccine candidate.

In the present study, Pušnik et al. investigated whether the XBB.1.5-adapted booster can overcome the persistent imprinting of SARS-CoV-2 immunity by wild-type based vaccines. The findings demonstrate increased plasma neutralization against the homologous variant following the booster vaccination. Formation of de novo humoral response against the mutated epitopes of XBB.1.5 variant's surface proteins was observed in 3/20 individuals. The booster vaccination had no significant effect on T-cell response.

The only currently licensed vaccine against tuberculosis (TB), Bacille Calmette Guérin (BCG), is insufficient to control the epidemic. MTBVAC is a live attenuated strain of Mycobacterium tuberculosis (M.tb) and is one the most advanced TB vaccine candidates in the pipeline. It is more efficacious than BCG in preclinical models including non-human primates (NHPs), and has demonstrated safety and immunogenicity in human populations. To better understand the immune mechanisms underlying the superior efficacy conferred by MTBVAC, we characterized M.tb-specific antibody responses in NHPs vaccinated with either BCG or MTBVAC. MTBVAC vaccination induced higher titers of IgG, IgM and IgA, and higher avidity IgG compared with BCG vaccination. IgG avidity correlated with protection following M.tb challenge in the same animals, validating the association previously reported between this measure and protection in the context of intravenous BCG vaccination, suggesting that IgG avidity may represent a relevant marker or correlate of protection from TB.

As SARS-CoV-2 evolves, increasing in potential for greater transmissibility and immune escape, updated vaccines are needed to boost adaptive immunity to protect against COVID-19 caused by circulating strains. Here, we report features of the monovalent Omicron XBB.1.5-adapted BNT162b2 vaccine, which contains XBB.1.5-specific sequence changes, relative to the original BNT162b2 backbone, in the encoded prefusion-stabilized SARS-CoV-2 spike protein (S(P2)). Biophysical characterization of Omicron XBB.1.5 S(P2) demonstrated that it maintains a prefusion conformation and adopts a flexible, predominantly open, state, with high affinity for the human ACE-2 receptor. When administered as a 4th dose in BNT162b2-experienced mice, the monovalent Omicron XBB.1.5 vaccine elicited substantially higher serum neutralizing titers against pseudotyped viruses of Omicron XBB.1.5, XBB.1.16, XBB.1.16.1, XBB.2.3, EG.5.1 and HV.1 sublineages and phylogenetically distant BA.2.86 lineage than the bivalent Wild Type + Omicron BA.4/5 vaccine. Similar trends were observed against Omicron XBB sublineage pseudoviruses when the vaccine was administered as a 2-dose series in naive mice. Strong S-specific Th1 CD4⁺ and IFNγ⁺ CD8⁺ T cell responses were also observed. These findings, together with real world performance of the XBB.1.5-adapted vaccine, suggest that preclinical data for the monovalent Omicron XBB.1.5-adapted BNT162b2 was predictive of protective immunity against dominant SARS-CoV-2 strains.

Neuraminidase (NA), the second most abundant surface glycoprotein on the influenza virus, plays a key role in viral replication and propagation. Despite growing evidence showing that NA-specific antibodies correlate with resistance to disease in humans, current licensed vaccines focus almost entirely on the hemagglutinin (HA) antigen. Here, we demonstrate that recombinant NA (rNA) protein is highly immunogenic in both naïve mice and ferrets, as well as in pre-immune ferrets, irrespective of the level of match with preexisting immunity. Ferrets vaccinated with rNA developed mild influenza disease symptoms upon challenge with human H3N2 influenza virus, and anti-NA antibody responses appeared correlated with reduction in disease severity. The addition of rNA to a quadrivalent HA-based vaccine induced robust NA-specific humoral immunity in ferrets, while retaining the ability to induce HA-specific immunity. These results demonstrate that the addition of rNA is a viable option to increase immunogenicity and potentially efficacy versus currently licensed influenza vaccines by means of boosting NA immunity.

Rotarix® vaccine was introduced into the Malawi national immunization program in October 2012. We analyzed data on children <5 years old hospitalized with acute gastroenteritis from January 2012 to June 2022, and compared to pre-vaccination data from 1997 to 2009. We estimated vaccine coverage before, during, and after the COVID-19 pandemic using data from rotavirus-negative children. We compared the observed weekly number of rotavirus-associated gastroenteritis (RVGE) cases by age to predictions from a previously developed mathematical model to estimate overall vaccine effectiveness. The number of RVGE and rotavirus-negative acute gastroenteritis cases declined substantially following vaccine introduction. Vaccine coverage among rotavirus-negative controls was >90% with two doses by July 2014, and declined to a low of ~80% in October 2020 before returning to pre-pandemic levels by July 2021. Our models captured the post-vaccination trends in RVGE incidence. Comparing observed RVGE cases to the model-predicted incidence without vaccination, overall effectiveness was estimated to be modest at 36.0% (95% prediction interval: 33.6%, 39.9%), peaking in 2014, and was highest in infants (52.5%; 95% prediction interval: 50.1%, 54.9%). Our mathematical models provide a validated platform for assessing strategies to improve rotavirus vaccine impact in low-income settings.

Obesity is a recognized factor influencing immune function and infectious disease outcomes. Characterization of the influence of obesity on SARS-CoV-2 humoral vaccine immunogenicity is required to properly tailor vaccine type (mRNA, viral-vector, protein subunit vaccines) and dosing schedule. Data from a prospective cohort study collected over 34 months was used to evaluate the slope of antibody production and decay and neutralizing capacity following SARS-CoV-2 vaccination in individuals with and without obesity at baseline. Most participants were female (65.4%), white (92.4%), and received mRNA vaccines. 210 were obese and 697 non-obese. Sex and infection-acquired immunity were identified as effect modifiers for the relationship between obesity and COVID-19 vaccine humoral immunogenicity. No consistent influence of obesity on peak titres, titre retention, antibody isotype (IgG, IgM, IgA), or neutralization was identified when controlling for other key variables. It may not be necessary to consider this variable when developing SARS-CoV-2 vaccine dosing strategies.

RTS,S and R21 are the only vaccines recommended by the WHO to protect children from Plasmodium falciparum (Pf) clinical malaria. Both vaccines target the Pf sporozoite surface protein circumsporozoite protein (CSP). Recent studies showed that human antibodies neutralize Pf sporozoites most efficiently when simultaneously binding to the PfCSP NANP repeat and the NPDP junction domain. However, neither RTS,S nor R21 targets this junction domain. To test the potential of the NPDP junction domain and other sites of PfCSP as innovative vaccine targets, we developed multiple vaccine candidates based on cucumber mosaic virus-like particles (CuMV_TT-VLPs). These candidates vary in several aspects: the number of targeted NANP repeats, the presence or absence of the junction domain, the cleavage site, and up to three NVDP repeats within the target sequence. Immunogenicity and efficacy studies were conducted in BALB/c mice, utilizing chimeric Plasmodium berghei (Pb) sporozoites, in which the endogenous CSP has been replaced by PfCSP (Pb/PfCSP). We observed a positive association between the number of targeted NANP repeats and the induction of specific IgM/IgG antibodies. Elevated humoral responses led to enhanced protection against parasitemia after Pb/PfCSP sporozoite challenge. Especially high-avidity/affinity antibody formation and vaccine protection were NANP repeat-dependent. Intriguingly, vaccine efficacy was not enhanced by targeting sites on PfCSP other than the NANP repeats. Our data emphasize the dominant role of the NANP repeat region for induction of protective antibodies. Furthermore, we present here novel malaria vaccine candidates with an excellent immunogenic profile that confer sterile protection in mice, even in absence of adjuvants.

The 4CMenB (Bexsero^R) vaccine contains detergent-extracted outer membrane vesicles (OMVs) from a Neisseria meningitidis (Nm) group B strain NZ98/254 and three recombinant Nm protein antigens: Neisseria adhesin A (NadA), Factor H binding protein (FHbp, as the C-terminal protein in the GNA2091-FHbp fusion), and Neisserial Heparin Binding Antigen (NHBA, as the N-terminal protein in the NHBA-GNA1030 fusion). Previous work has shown that 4CMenB generates serum antibodies to Nm and Neisseria gonorrhoeae (Ng) OMV proteins and lipooligosaccharide (LOS). Mounting evidence indicates 4CMenB can partially protect against mucosal infections with Ng. The immunologic basis for Ng cross protection remains to be fully elucidated. Ten paired human sera obtained pre- and post-immunization with 4CMenB (1 month after a third vaccine dose) were used in ELISAs and in Western blots to determine IgG and IgA serum responses to OMVs from Nm strain NZ98/254 (OMV_Nm) and two Ng strains, 1291 and CNG20 (OMV_Ng), and gonococcal recombinant NHBA (rNHBA_Ng) proteins. Post 4CMenB sera, but not pre-sera, showed strong IgG and variable IgA responses to the OMV_Nm but lower (2-11-fold difference in signal intensity) recognition of OMV_Ng. All post (not pre) 4CMenB sera showed strong IgG, but variable IgA, recognition of rNHBA_Ng by ELISAs and Western blots. Three post 4CMenB sera at 10% (v/v) concentration had serum bactericidal activity (SBA) against Ng strains 1291 and CNG20 (~30-40% killing), not seen in paired pre-sera. These data confirmed 4CMenB-induced cross-reactive functional antibody responses to Ng. In competitive SBA assays, in which sera were pre-incubated with rNHBA, minimal SBA against Nm strain NZ98/254 was titrated away. However, most of the SBA against Ng strains 1291 and CNG20 required NHBA-specific antibodies, and the Δnhba mutants were resistant to killing by post 4CMenB sera. Removing NHBA-specific and LOS-specific OMV antibodies simultaneously decreased SBA significantly more than the sum of removing individual antibodies alone, suggesting synergy between anti-NHBA and anti-OMV antibodies. Anti- NHBA_Nm antibodies induced by 4CMenB vaccination cross react with NHBA_Ng and substantially contribute to the bactericidal response toward Ng induced by the vaccine.