Search

Annual administration and reformulation of influenza vaccines is required for protection against seasonal infections. However, the induction of strong and long-lasting T cells is critical to reach broad and potentially lifelong antiviral immunity. The NLRP3 inflammasome and its product interleukin-1β (IL-1β) are pivotal mediators of cellular immune responses to influenza, yet, overactivation of these systems leads to side effects, which hamper clinical applications. Here, we present a bypass around these toxicities by targeting the activity of IL-1β to CD8+ T cells. Using this approach, we demonstrate safe inclusion of IL-1β as an adjuvant in vaccination strategies, leading to full protection of mice against a high influenza virus challenge dose by raising potent T cell responses. In conclusion, this paper proposes a class of IL-1β-based vaccine adjuvants and also provides further insight in the mechanics of cellular immune responses driven by IL-1β. [ABSTRACT FROM AUTHOR]

A randomized, active-controlled, double-blind, first-in-human, phase 1 study was conducted in healthy Korean adults to evaluate the safety, tolerability, and immunogenicity of EuNmCV-5, a new pentavalent meningococcal vaccine targeting serogroups A, C, W, X, and Y. Sixty participants randomly received a single dose of either EuNmCV-5 or MenACWY-CRM, a quadrivalent vaccine containing serogroups A, C, W, and Y. Safety was assessed through monitoring anaphylactic reactions, adverse events for 28 days, and serious adverse events over 180 days. Immunogenicity was assessed via rabbit complement-dependent serum bactericidal antibody (rSBA) assay. EuNmCV-5 was safe, well-tolerated, and elicited a substantial antibody titer increase. The seroprotection rates exceeded 96.7%, and the seroconversion rates were over 85% for all the targeted serogroups. It showed higher seroconversion rates against serogroups A and C (p = 0.0016 and 0.0237, respectively) and elicited a substantial increase in GMT for all targeted serogroups compared to the MenACWY-CRM. ClinicalTrials.gov identifier: NCT05739292. [ABSTRACT FROM AUTHOR]

This study reports on the immunogenicity and biodistribution of H5 hemagglutinin (HA)-based self-amplifying (sa) mRNA vaccines in mice. Four sa-mRNA vaccines encoding either a secreted full-length HA, a secreted HA head domain, a secreted HA stalk domain, or a full-length membrane-anchored HA were investigated. All vaccines elicited an adaptive immune response. However, the full-length HA sa-RNA vaccines demonstrated superior performance compared to head and stalk domain vaccines. The antibody titers positively correlated with the vaccine dose. Cellular immune responses and antigen-specific IgA antibodies in the lungs were also observed. The comparison of the sa-mRNA vaccines encoding the secreted and membrane-anchored full-length HA revealed that anchoring of the HA to the membrane significantly enhanced the antibody and cellular responses. In addition to the injection site, the intramuscularly injected sa-mRNA-LNPs were also detected in the draining lymph nodes, spleen, and to a lesser extent, in the lung, kidney, liver, and heart. [ABSTRACT FROM AUTHOR]

The re-emergence of yellow fever (YF) urged new mass vaccination campaigns and, in 2017, the World Health Organization approved the use of the fractional dose (FD) of the YF vaccine due to stock shortage. In an observational cross-sectional investigation, we have assessed viremia, antibodies, soluble mediators and effector and memory T and B-cells induced by primary vaccination of volunteers with FD and standard dose (SD). Similar viremia and levels of antibodies and soluble markers were induced early after immunization. However, a faster decrease in the latter was observed after SD. The FD led to a sustained expansion of helper T-cells and an increased expression of activation markers on T-cells early after vaccination. Although with different kinetics, expansion of plasma cells was induced upon SD and FD immunization. Integrative analysis reveals that FD induces a more complex network involving follicular helper T cells and B-cells than SD. Our findings substantiate that FD can replace SD inducing robust correlates of protective immune response against YF. [ABSTRACT FROM AUTHOR]

Group A Streptococcus (GAS) is a significant human pathogen that poses a global health concern. However, the development of a GAS vaccine has been challenging due to the multitude of diverse M-types and the risk of triggering cross-reactive immune responses. Our previous research has identified a critical role of PrsA1 and PrsA2, surface post-translational molecular chaperone proteins, in maintaining GAS proteome homeostasis and virulence traits. In this study, we aimed to further explore the potential of PrsA1 and PrsA2 as vaccine candidates for preventing GAS infection. We found that PrsA1 and PrsA2 are highly conserved among GAS isolates, demonstrating minimal amino acid variation. Antibodies specifically targeting PrsA1/A2 showed no cross-reactivity with human heart proteins and effectively enhanced neutrophil opsonophagocytic killing of various GAS serotypes. Additionally, passive transfer of PrsA1/A2-specific antibodies conferred protective immunity in infected mice. Compared to alum, immunization with CFA-adjuvanted PrsA1/A2 induced higher levels of Th1-associated IgG isotypes and complement activation and provided approximately 70% protection against invasive GAS challenge. These findings highlight the potential of PrsA1 and PrsA2 as universal vaccine candidates for the development of an effective GAS vaccine. [ABSTRACT FROM AUTHOR]

The human papillomavirus minor capsid protein L2 is being extensively explored in pre-clinical studies as an attractive vaccine antigen capable of inducing broad-spectrum prophylactic antibody responses. Recently, we have developed two HPV vaccine antigens – PANHPVAX and CUT-PANHPVAX- both based on heptameric nanoparticle antigens displaying polytopes of the L2 major cross-neutralizing epitopes of eight mucosal and twelve cutaneous HPV types, respectively. Prompted by the variable neutralizing antibody responses against some of the HPV types targeted by the antigens observed in previous studies, here we investigated the influence on immunogenicity of six distinct glycine-proline spacers inserted upstream to a specific L2 epitope. We show that spacer variants differentially influence antigen immunogenicity in a mouse model, with the antigen constructs M8merV6 and C12merV6 displaying a superior ability in the induction of neutralizing antibodies as determined by pseudovirus-based neutralization assays (PBNAs). L2-peptide enzyme-linked immunosorbent assay (ELISA) assessments determined the total anti-L2 antibody level for each antigen variant, showing for the majority of sera a correlation with their repective neutralizing antibody level. Surface Plasmon Resonance revealed that L2 epitope-specific, neutralizing monoclonal antibodies (mAbs) display distinct avidities to different antigen spacer variants. Furthermore, mAb affinity toward individual spacer variants was well correlated with their neutralizing antibody induction capacity, indicating that the mAb affinity assay predicts L2-based antigen immunogenicity. These observations provide insights on the development and optimization of L2-based HPV vaccines. [ABSTRACT FROM AUTHOR]

AKS-452, a subunit vaccine comprising an Fc fusion of the ancestral wild-type (WT) SARS-CoV-2 virus spike protein receptor binding domain (SP/RBD), was evaluated without adjuvant in a single cohort, non-randomized, open-labelled phase II study (NCT05124483) at a single site in The Netherlands for safety and immunogenicity. A single 90 µg subcutaneous booster dose of AKS-452 was administered to 71 adults previously primed with a registered mRNA- or adenovirus-based vaccine and evaluated for 273 days. All AEs were mild and no SAEs were attributable to AKS-452. While all subjects showed pre-existing SP/RBD binding and ACE2-inhibitory IgG titers, 60–68% responded to AKS-452 via ≥2-fold increase from days 28 to 90 and progressively decreased back to baseline by day 180 (days 28 and 90 mean fold-increases, 14.7 ± 6.3 and 8.0 ± 2.2). Similar response kinetics against RBD mutant proteins (including omicrons) were observed but with slightly reduced titers relative to WT. There was an expected strong inverse correlation between day-0 titers and the fold-increase in titers at day 28. AKS-452 enhanced neutralization potency against live virus, consistent with IgG titers. Nucleocapsid protein (Np) titers suggested infection occurred in 66% (46 of 70) of subjects, in which only 20 reported mild symptomatic COVID-19. These favorable safety and immunogenicity profiles support booster evaluation in a planned phase III universal booster study of this room-temperature stable vaccine that can be rapidly and inexpensively manufactured to serve vaccination at a global scale without the need of a complex distribution or cold chain. [ABSTRACT FROM AUTHOR]

The quantitation of antibody responses is a critical requirement for the successful development of vaccines and therapeutics that often relies on the use of standardized reference materials to determine relative quantities within biological samples. The validity of comparing responses across assays using arbitrarily defined reference values is therefore limited. We developed a generalizable method known as MASCALE (Mass Spectrometry Enabled Conversion to Absolute Levels of ELISA Antibodies) for absolute quantitation of antibodies by calibrating ELISA reference sera using mass spectrometry. Levels of proteotypic peptides served as a proxy for human IgG, allowing the conversion of responses from arbitrary values to absolute amounts. Applications include comparison of binding assays at two separate laboratories and evaluation of cross-clade magnitude-breadth responses induced by an investigational HIV-1 vaccine regimen. MASCALE addresses current challenges in the interpretation of immune responses in clinical trials and expands current options available to make suitable comparisons across different settings. [ABSTRACT FROM AUTHOR]

Malaria transmission-blocking vaccines (TBV) are designed to inhibit the sexual stage development of the parasite in the mosquito host and can play a significant role in achieving the goal of malaria elimination. Preclinical and clinical studies using protein–protein conjugates of leading TBV antigens Pfs25 and Pfs230 domain 1 (Pfs230D1) have demonstrated the feasibility of TBV. Nevertheless, other promising vaccine platforms for TBV remain underexplored. The recent success of mRNA vaccines revealed the potential of this technology for infectious diseases. We explored the mRNA platform for TBV development. mRNA constructs of Pfs25 and Pfs230D1 variously incorporating signal peptides (SP), GPI anchor, and Trans Membrane (TM) domain were assessed in vitro for antigen expression, and selected constructs were evaluated in mice. Only mRNA constructs with GPI anchor or TM domain that resulted in high cell surface expression of the antigens yielded strong immune responses in mice. These mRNA constructs generated higher transmission-reducing functional activity versus the corresponding alum-adjuvanted protein-protein conjugates used as comparators. Pfs25 mRNA with GPI anchor or TM maintained >99% transmission reducing activity through 126 days, the duration of the study, demonstrating the potential of mRNA platform for TBV. [ABSTRACT FROM AUTHOR]

Measuring SARS-CoV-2-specific T cell responses is crucial to understanding an individual's immunity to COVID-19. However, high inter- and intra-assay variability make it difficult to define T cells as a correlate of protection against COVID-19. To address this, we performed systematic review and meta-analysis of 495 datasets from 94 original articles evaluating SARS-CoV-2-specific T cell responses using three assays – Activation Induced Marker (AIM), Intracellular Cytokine Staining (ICS), and Enzyme-Linked Immunospot (ELISPOT), and defined each assay's quantitative range. We validated these ranges using samples from 193 SARS-CoV-2-exposed individuals. Although IFNγ ELISPOT was the preferred assay, our experimental validation suggested that it under-represented the SARS-CoV-2-specific T cell repertoire. Our data indicate that a combination of AIM and ICS or FluoroSpot assay would better represent the frequency, polyfunctionality, and compartmentalization of the antigen-specific T cell responses. Taken together, our results contribute to defining the ranges of antigen-specific T cell assays and propose a choice of assay that can be employed to better understand the cellular immune response against viral diseases. [ABSTRACT FROM AUTHOR]

Fractional dosing can be a cost-effective vaccination strategy to accelerate individual and herd immunity in a pandemic. We assessed the immunogenicity and safety of primary intradermal (ID) vaccination, with a 1/5th dose compared with the standard intramuscular (IM) dose of mRNA-1273 in SARS-CoV-2 naïve persons. We conducted an open-label, non-inferiority, randomized controlled trial in the Netherlands between June and December 2021. One hundred and fifty healthy and SARS-CoV-2 naïve participants, aged 18–30 years, were randomized (1:1:1) to receive either two doses of 20 µg mRNA-1273 ID with a standard needle (SN) or the Bella-mu® needle (BM), or two doses of 100 µg IM, 28 days apart. The primary outcome was non-inferiority in seroconversion rates at day 43 (D43), defined as a neutralizing antibody concentration threshold of 465 IU/mL, the lowest response in the IM group. The non-inferiority margin was set at −15%. Neutralizing antibody concentrations at D43 were 1789 (95% CI: 1488–2150) in the IM and 1263 (951–1676) and 1295 (1020–1645) in the ID-SN and ID-BM groups, respectively. The absolute difference in seroconversion proportion between fractional and standard-dose groups was −13.95% (−24.31 to −3.60) for the ID-SN and −13.04% (−22.78 to −3.31) for the ID-BM group and exceeded the predefined non-inferiority margin. Although ID vaccination with 1/5th dose of mRNA-1273 did not meet the predefined non-inferior criteria, the neutralizing antibody concentrations in these groups are far above the proposed proxy for protection against severe disease (100 IU/mL), justifying this strategy in times of vaccine scarcity to accelerate mass protection against severe disease. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) causes a high disease burden in older adults. An effective vaccine for this RSV-primed population may need to boost/elicit robust RSV-neutralizing antibody responses and recall/induce RSV-specific T cell responses. To inform the selection of the vaccine formulation for older adults, RSVPreF3 (RSV fusion glycoprotein engineered to maintain the prefusion conformation) with/without AS01 adjuvant was evaluated in mice and bovine RSV infection-primed cattle. In mice, RSVPreF3/AS01 elicited robust RSV-A/B-specific neutralization titers and RSV F-specific polyfunctional CD4+ T cell responses exceeding those induced by non-adjuvanted RSVPreF3. In primed bovines, RSVPreF3/AS01 tended to induce higher pre-/post-vaccination fold-increases in RSV-A/B-specific neutralization titers relative to non-adjuvanted and Alum-adjuvanted RSVPreF3 formulations, and elicited higher RSV F-specific CD4+ T cell frequencies relative to the non-adjuvanted vaccine. Though AS01 adjuvanticity varied by animal species and priming status, RSVPreF3/AS01 elicited/boosted RSV-A/B-specific neutralization titers and RSV F-specific CD4+ T cell responses in both animal models, which supported its further clinical evaluation as prophylactic candidate vaccine for older adults. [ABSTRACT FROM AUTHOR]

With the large-scale vaccination of lipid nanoparticles (LNP)-based COVID-19 mRNA vaccines, elucidating the potential polyethylene glycol (PEG)-associated immune responses triggered by clinically relevant LNP has become imminent. However, inconsistent findings were observed across very limited population-based studies. Herein we initiated a study using LNP carrier of Comirnaty® as a representative, and simulated real-world clinical practice covering a series of time points and various doses correlated with approved LNP-delivered drugs in a rat model. We demonstrated the time- and dose-dependency of LNP-induced anti-PEG antibodies in rats. As a thymus-independent antigen, LNP unexpectedly induced isotype switch and immune memory, leading to rapid enhancement and longer lasting time of anti-PEG IgM and IgG upon re-injection in rats. Importantly, initial LNP injection accelerated the blood clearance of subsequent dosing in rats. These findings refine our understandings on LNP and possibly other PEG derivatives, and may promote optimization of related premarket guidelines and clinical protocols. [ABSTRACT FROM AUTHOR]

Understanding the balance between epitope shielding and accessibility on HIV-1 envelope (Env) trimers is essential to guide immunogen selection for broadly neutralizing antibody (bnAb) based vaccines. To investigate the antigenic space of Env immunogens, we created a strategy based on synthetic, high diversity, Designed Ankyrin Repeat Protein (DARPin) libraries. We show that DARPin Antigenicity Analysis (DANA), a purely in vitro screening tool, has the capability to extrapolate relevant information of antigenic properties of Env immunogens. DANA screens of stabilized, soluble Env trimers revealed that stronger trimer stabilization led to the selection of highly mutated DARPins with length variations and framework mutations mirroring observations made for bnAbs. By mimicking heterotypic prime-boost immunization regimens, DANA may be used to select immunogen combinations that favor the selection of trimer-reactive binders. This positions DANA as a versatile strategy for distilling fundamental antigenic features of immunogens, complementary to preclinical immunogenicity testing. [ABSTRACT FROM AUTHOR]

In response to COVID-19 pandemic, we have launched a vaccine development program against SARS-CoV-2. Here we report the safety, tolerability, and immunogenicity of a recombinant protein RBD fusion heterodimeric vaccine against SARS-CoV-2 (PHH-1V) evaluated in a phase 1-2a dose-escalation, randomized clinical trial conducted in Catalonia, Spain. 30 young healthy adults were enrolled and received two intramuscular doses, 21 days apart of PHH-1V vaccine formulations [10 µg (n = 5), 20 µg (n = 10), 40 µg (n = 10)] or control [BNT162b2 (n = 5)]. Each PHH-1V group had one safety sentinel and the remaining participants were randomly assigned. The primary endpoint was solicited events within 7 days and unsolicited events within 28 days after each vaccination. Secondary endpoints were humoral and cellular immunogenicity against the variants of concern (VOCs) alpha, beta, delta and gamma. All formulations were safe and well tolerated, with tenderness and pain at the site of injection being the most frequently reported solicited events. Throughout the study, all participants reported having at least one mild to moderate unsolicited event. Two unrelated severe adverse events (AE) were reported and fully resolved. No AE of special interest was reported. Fourteen days after the second vaccine dose, all participants had a >4-fold change in total binding antibodies from baseline. PHH-1V induced robust humoral responses with neutralizing activities against all VOCs assessed (geometric mean fold rise at 35 days p < 0.0001). The specific T-cell response assessed by ELISpot was moderate. This initial evaluation has contributed significantly to the further development of PHH-1V, which is now included in the European vaccine portfolio. ClinicalTrials.gov Identifier NCT05007509 EudraCT No. 2021-001411-82 [ABSTRACT FROM AUTHOR]

Syphilis has resurged in many countries, which has called attention to vaccine development. Based on the immunization-based rabbit model of infection with the Nichols strain, this study explored the protective immune response of a controversial syphilis vaccine candidate, TprK, and found that immunization with full-length rTprK was effective in attenuating lesion development and accelerating lesion resolution, which could reduce the probability of the pathogen spreading to distant tissue sites to prevent the progression of the disease to some extent. Furthermore, the results revealed that immunization with rTprK not only rapidly induced a strong Th1-like cellular response but also elicited a humoral immune response to produce opsonic antibodies to enhance macrophage-mediated opsonophagocytosis. Although complete protection against infection was not achieved, the study provided a comprehensive and in-depth exploration of the immunogenicity of TprK and highlighted the importance of TprK as a promising syphilis vaccine component. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) causes a high disease burden in older adults. An effective vaccine for this RSV-primed population may need to boost/elicit robust RSV-neutralizing antibody responses and recall/induce RSV-specific T cell responses. To inform the selection of the vaccine formulation for older adults, RSVPreF3 (RSV fusion glycoprotein engineered to maintain the prefusion conformation) with/without AS01 adjuvant was evaluated in mice and bovine RSV infection-primed cattle. In mice, RSVPreF3/AS01 elicited robust RSV-A/B-specific neutralization titers and RSV F-specific polyfunctional CD4+ T cell responses exceeding those induced by non-adjuvanted RSVPreF3. In primed bovines, RSVPreF3/AS01 tended to induce higher pre-/post-vaccination fold-increases in RSV-A/B-specific neutralization titers relative to non-adjuvanted and Alum-adjuvanted RSVPreF3 formulations, and elicited higher RSV F-specific CD4+ T cell frequencies relative to the non-adjuvanted vaccine. Though AS01 adjuvanticity varied by animal species and priming status, RSVPreF3/AS01 elicited/boosted RSV-A/B-specific neutralization titers and RSV F-specific CD4+ T cell responses in both animal models, which supported its further clinical evaluation as prophylactic candidate vaccine for older adults. [ABSTRACT FROM AUTHOR]

Formyl peptide receptor-like 1 inhibitor protein (FLIPr) is an immune evasion protein produced by Staphylococcus aureus, and FLIPr is a potential vaccine candidate for reducing Staphylococcus aureus virulence and biofilm formation. We produced recombinant lipidated FLIPr (rLF) to increase the immunogenicity of FLIPr and showed that rLF alone elicited potent anti-FLIPr antibody responses to overcome the FLIPr-mediated inhibition of phagocytosis. In addition, rLF has potent immunostimulatory properties. We demonstrated that rLF is an effective adjuvant. When an antigen is formulated with rLF, it can induce long-lasting antigen-specific immune responses and enhance mucosal and systemic antibody responses as well as broad-spectrum T-cell responses in mice. These findings support further exploration of rLF in the clinic as an adjuvant for various vaccine types with extra benefits to abolish FLIPr-mediated immunosuppressive effects. [ABSTRACT FROM AUTHOR]

Immunization with the Amastigote Surface Protein-2 (ASP-2) and Trans-sialidase (TS) antigens either in the form of recombinant protein, encoded in plasmids or human adenovirus 5 (hAd5) confers robust protection against various lineages of Trypanosoma cruzi. Herein we generated a chimeric protein containing the most immunogenic regions for T and B cells from TS and ASP-2 (TRASP) and evaluated its immunogenicity in comparison with our standard protocol of heterologous prime-boost using plasmids and hAd5. Mice immunized with TRASP protein associated to Poly-ICLC (Hiltonol) were highly resistant to challenge with T. cruzi, showing a large decrease in tissue parasitism, parasitemia and no lethality. This protection lasted for at least 3 months after the last boost of immunization, being equivalent to the protection induced by DNA/hAd5 protocol. TRASP induced high levels of T. cruzi-specific antibodies and IFNγ-producing T cells and protection was primarily mediated by CD8+ T cells and IFN-γ. We also evaluated the toxicity, immunogenicity, and efficacy of TRASP and DNA/hAd5 formulations in dogs. Mild collateral effects were detected at the site of vaccine inoculation. While the chimeric protein associated with Poly-ICLC induced high levels of antibodies and CD4+ T cell responses, the DNA/hAd5 induced no antibodies, but a strong CD8+ T cell response. Immunization with either vaccine protected dogs against challenge with T. cruzi. Despite the similar efficacy, we conclude that moving ahead with TRASP together with Hiltonol is advantageous over the DNA/hAd5 vaccine due to pre-existing immunity to the adenovirus vector, as well as the cost-benefit for development and large-scale production. [ABSTRACT FROM AUTHOR]

A novel Influenza A virus (subtype H7N9) emerged in spring 2013 and caused considerable mortality in zoonotically infected patients. To be prepared for potential pandemics, broadly effective and safe vaccines are crucial. Recombinant measles virus (MeV) encoding antigens of foreign pathogens constitutes a promising vector platform to generate novel vaccines. To characterize the efficacy of H7N9 antigens in a prototypic vaccine platform technology, we generated MeVs encoding either neuraminidase (N9) or hemagglutinin (H7). Moraten vaccine strain-derived vaccine candidates were rescued; they replicated with efficiency comparable to that of the measles vaccine, robustly expressed H7 and N9, and were genetically stable over 10 passages. Immunization of MeV-susceptible mice triggered the production of antibodies against H7 and N9, including hemagglutination-inhibiting and neutralizing antibodies induced by MVvac2-H7(P) and neuraminidase-inhibiting antibodies by MVvac2-N9(P). Vaccinated mice also developed long-lasting H7- and N9-specific T cells. Both MVvac2-H7(P) and MVvac2-N9(P)-vaccinated mice were protected from lethal H7N9 challenge. [ABSTRACT FROM AUTHOR]

The opportunistic pathogen Pseudomonas aeruginosa (Pa) causes severe nosocomial infections, especially in immunocompromised individuals and the elderly. Increasing drug resistance, the absence of a licensed vaccine and increased hospitalizations due to SARS-CoV-2 have made Pa a major healthcare risk. To address this, we formulated a candidate subunit vaccine against Pa (L-PaF), by fusing the type III secretion system tip and translocator proteins with LTA1 in an oil-in-water emulsion (ME). This was mixed with the TLR4 agonist (BECC438b). Lung mRNA sequencing showed that the formulation activates genes from multiple immunological pathways eliciting a protective Th1-Th17 response following IN immunization. Following infection, however, the immunized mice showed an adaptive response while the PBS-vaccinated mice experienced rapid onset of an inflammatory response. The latter displayed a hypoxic lung environment with high bacterial burden. Finally, the importance of IL-17 and immunoglobulins were demonstrated using knockout mice. These findings suggest a need for a balanced humoral and cellular response to prevent the onset of Pa infection and that our formulation could elicit such a response. [ABSTRACT FROM AUTHOR]

Despite the success of the widely used attenuated yellow fever (YF) vaccine, its global supply remains a substantial barrier to implementing vaccination campaigns in endemic regions and combating emerging epidemics. In A129 mice and rhesus macaques, we evaluated the immunogenicity and protective activity of messenger RNA (mRNA) vaccine candidates encapsulated in lipid nanoparticles, expressing the pre-membrane and envelope proteins or the non-structural protein 1 of YF virus. Vaccine constructs induced humoral and cell-mediated immune responses in mice, resulting in protection against lethal YF virus infection after passive administration of serum or splenocytes from vaccinated mice. Vaccination of macaques induced sustained high humoral and cellular immune responses for at least 5 months after the second dose. Our data demonstrate that these mRNA vaccine candidates can be considered an attractive addition to the licensed YF vaccine supply based on the induction of functional antibodies correlating with protection and T-cell responses; they could alleviate the limited supply of current YF vaccines, mitigating future YF epidemics. [ABSTRACT FROM AUTHOR]

Development of SARS-CoV-2 vaccines that protect vulnerable populations is a public health priority. Here, we took a systematic and iterative approach by testing several adjuvants and SARS-CoV-2 antigens to identify a combination that elicits antibodies and protection in young and aged mice. While demonstrating superior immunogenicity to soluble receptor-binding domain (RBD), RBD displayed as a protein nanoparticle (RBD-NP) generated limited antibody responses. Comparison of multiple adjuvants including AddaVax, AddaS03, and AS01B in young and aged mice demonstrated that an oil-in-water emulsion containing carbohydrate fatty acid monosulphate derivative (CMS:O/W) most effectively enhanced RBD-NP-induced cross-neutralizing antibodies and protection across age groups. CMS:O/W enhanced antigen retention in the draining lymph node, induced injection site, and lymph node cytokines, with CMS inducing MyD88-dependent Th1 cytokine polarization. Furthermore, CMS and O/W synergistically induced chemokine production from human PBMCs. Overall, CMS:O/W adjuvant may enhance immunogenicity and protection of vulnerable populations against SARS-CoV-2 and other infectious pathogens. [ABSTRACT FROM AUTHOR]

Development of SARS-CoV-2 vaccines that protect vulnerable populations is a public health priority. Here, we took a systematic and iterative approach by testing several adjuvants and SARS-CoV-2 antigens to identify a combination that elicits antibodies and protection in young and aged mice. While demonstrating superior immunogenicity to soluble receptor-binding domain (RBD), RBD displayed as a protein nanoparticle (RBD-NP) generated limited antibody responses. Comparison of multiple adjuvants including AddaVax, AddaS03, and AS01B in young and aged mice demonstrated that an oil-in-water emulsion containing carbohydrate fatty acid monosulphate derivative (CMS:O/W) most effectively enhanced RBD-NP-induced cross-neutralizing antibodies and protection across age groups. CMS:O/W enhanced antigen retention in the draining lymph node, induced injection site, and lymph node cytokines, with CMS inducing MyD88-dependent Th1 cytokine polarization. Furthermore, CMS and O/W synergistically induced chemokine production from human PBMCs. Overall, CMS:O/W adjuvant may enhance immunogenicity and protection of vulnerable populations against SARS-CoV-2 and other infectious pathogens. [ABSTRACT FROM AUTHOR]

Long-term immunity after HBV vaccination is still debated. When assessing immune persistence, several variables must be considered, the clear definition of which is crucial. Our aim was to assess protection 10–20 years after primary vaccination and to estimate the effect of age at first dose, sex and time elapsed between doses on long-term protection. We conducted a retrospective cohort study between January 2004 and December 2020. Antibody titres above 10 IU/L were considered protective. Geometric mean titres (GMT) were calculated. The effect of the above variables on long-term protection was assessed by logistic regression analysis. Included participants were 9459. Among those vaccinated during infancy, GMT gradually increased from 11 IU/L (first dose in 1st trimester of life) to 68 IU/L (4th trimester), while the proportion of individuals <10 IU/L remained stable between 1st and 2nd trimester (51%) and it decreased substantially in 3rd (28%) and even more so in the 4th (18%). A one-month delay in first and third dose administration was correlated with a −16% (AOR: 0.84; 95% CI: 0.78–0.91) and a −11% (AOR: 0.89; 95% CI: 0.85–0.94) risk of a titre <10 IU/L, respectively, ~20 years after immunisation. In contrast, similar changes do not comparably affect vaccination in adolescence. The start of vaccination at the third month of age is a compromise between the development of acceptable immunogenicity and the need to protect the infant as early as possible. However, the chance of slightly delaying the vaccine administration within the first year of life may be considered given the impact on long-term persistence of anti-HBs. [ABSTRACT FROM AUTHOR]

Yellow fever, a mosquito-borne flavivirus infection, is an important public health problem in Africa and Latin America. A Yellow Fever vaccine (YFV) was developed and tested in a study in India. This was a Phase I, open-label, randomized, controlled study where healthy adults received SII YFV intramuscularly (SII YFV IM), SII YFV subcutaneously (SII YFV SC) or STAMARIL® (Sanofi-Pasteur) in 1:1:1 ratio. They were followed for solicited reactions for 10 days and unsolicited events for 28 days and serious adverse events for 3 months. YF-neutralizing antibodies were measured at baseline and on Days 10, 14, 28. A total of 60 adults were enrolled in the study. The proportion of participants with solicited reactions was 10%, 40%, and 25% in SII YFV SC, SII YFV IM, and STAMARIL® arms, respectively. No causally related unsolicited events or any serious adverse event was reported. After vaccination, the seroconversion was 94.44%, 100%, and 100%, in the three arms respectively. The post-vaccination geometric mean titers were similar in the study arms. The new YFV was found safe and immunogenic by IM as well as SC routes. The vaccine can be tested in further phases of clinical studies. [ABSTRACT FROM AUTHOR]

Adolescents and children play an important role in SARS-CoV-2 transmission and epidemiology. MVC-COV1901 is a subunit SARS-CoV-2 vaccine based on stabilized spike protein adjuvanted with CpG 1018 and aluminum hydroxide that has received emergency use approval (EUA) for adults in Taiwan. In this study, we have investigated the safety and immunogenicity of two doses of MVC-COV1901 in adolescents. Healthy adolescents from the age of 12–17 years were randomly assigned to receive two intramuscular doses of either MVC-COV1901 or placebo at 28 days apart. Adverse events were mostly mild and were similar in MVC-COV1901 and placebo groups, with the most commonly reported adverse events being pain/tenderness and malaise/fatigue. All immunogenicity endpoints in the adolescent group were non-inferior to the endpoints seen in the young adult and placebo groups. The results here advocate the use of MVC-COV1901 in adolescents in the ongoing efforts to control the pandemic. ClinicalTrials.gov registration: NCT04951388. [ABSTRACT FROM AUTHOR]

In vaccinology, a potent immunogen has two prerequisite attributes—antigenicity and immunogenicity. We have rational designed a triple-type HPV vaccine against HPV58, −33 and −52 covered in Gardasil 9 based on the sequence homology and similar surface loop structure of L1 protein, which is related to cross-type antigenicity. Here, we design another triple-type vaccine against non-vaccine types HPV39, −68 and −70 by immunogenicity optimization considering type specific immunodominant epitopes located in separate region for different types. First, we optimized the expression of wild-type HPV39, −68 and −70 L1-only virus-like particles (VLPs) in E. coli through N-terminal truncation of HPV L1 proteins and non-fusion soluble expression. Second, based on genetic relationships and an L1 homologous loop-swapping rationale, we constructed several triple-type chimeric VLPs for HPV39, −68 and −70, and obtained the lead candidate named H39–68FG-70DE by the immunogenicity optimization using reactivity profile of a panel type-specific monoclonal antibodies. Through comprehensive characterization using various biochemical, VLP-based analyses and immune assays, we show that H39–68FG-70DE assumes similar particulate properties as that of its parental VLPs, along with comparable neutralization immunogenicity for all three HPV types. Overall, this study shows the promise and translatability of an HPV39/68/70 triple-type vaccine, and the possibility of expanding the type-coverage of current HPV vaccines. Our study further expanded the essential criteria on the rational design of a cross-type vaccine, i.e. separate sites with inter-type similar sequence and structure as well as type-specific immunodominant epitope to be clustered together. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic marks the third coronavirus pandemic this century (SARS-CoV-1, MERS, SARS-CoV-2), emphasizing the need to identify and evaluate conserved immunogens for a pan-sarbecovirus vaccine. Here we investigate the potential utility of a T-cell vaccine strategy targeting conserved regions of the sarbecovirus proteome. We identified the most conserved regions of the sarbecovirus proteome as portions of the RNA-dependent RNA polymerase (RdRp) and Helicase proteins, both of which are part of the coronavirus replication transcription complex (RTC). Fitness constraints suggest that as SARS-CoV-2 continues to evolve these regions may better preserve cross-reactive potential of T-cell responses than Spike, Nucleocapsid, or Membrane proteins. We sought to determine if vaccine-elicited T-cell responses to the highly conserved regions of the RTC would reduce viral loads following challenge with SARS-CoV-2 in mice using a rhesus adenovirus serotype 52 (RhAd52) vector. The RhAd52.CoV.Consv vaccine generated robust cellular immunity in mice and led to significant reductions in viral loads in the nasal turbinates following challenge with a mouse-adapted SARS-CoV-2. These data suggest the potential utility of T-cell targeting of conserved regions for a pan-sarbecovirus vaccine. [ABSTRACT FROM AUTHOR]

Pathological forms of Tau protein are directly associated with neurodegeneration and correlate with Alzheimer's Disease (AD) symptoms, progression, and severity. Previously, using various mouse models of Tauopathies and AD, we have demonstrated the immunogenicity and efficacy of the MultiTEP-based adjuvanted vaccine targeting the phosphatase activating domain (PAD) of Tau, AV-1980R/A. Here, we analyzed its immunogenicity in non-human primates (NHP), the closest phylogenic relatives to humans with a similar immune system, to initiate the transition of this vaccine into clinical trials. We have demonstrated that AV-1980R/A is highly immunogenic in these NHPs, activating a broad but unique to each monkey repertoire of MultiTEP-specific T helper (Th) cells that, in turn, activate B cells specific to PAD. The resulting anti-PAD IgG antibodies recognize pathological Tau tangles and Tau-positive neuritis in AD case brain sections with no staining in control non-AD cases. These published data and efficacy results support the AV-1980R/A vaccine progression to first-in-human clinical trials. [ABSTRACT FROM AUTHOR]

Immunization with vesicular stomatitis virus (VSV)-vectored COVID-19 vaccine candidates expressing the SARS-CoV-2 spike protein in place of the VSV glycoprotein relies implicitly on expression of the ACE2 receptor at the muscular injection site. Here, we report that such a viral vector vaccine did not induce protective immunity following intramuscular immunization of K18-hACE2 transgenic mice. However, when the viral vector was trans-complemented with the VSV glycoprotein, intramuscular immunization resulted in high titers of spike-specific neutralizing antibodies. The vaccinated animals were fully protected following infection with a lethal dose of SARS-CoV-2-SD614G via the nasal route, and partially protected if challenged with the SARS-CoV-2Delta variant. While dissemination of the challenge virus to the brain was completely inhibited, replication in the lung with consequent lung pathology was not entirely controlled. Thus, intramuscular immunization was clearly enhanced by trans-complementation of the VSV-vectored vaccines by the VSV glycoprotein and led to protection from COVID-19, although not achieving sterilizing immunity. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) G glycoprotein has recently reemerged as a vaccine antigen due to its ability to elicit potent neutralizing antibodies and ameliorate disease in animal models. Here we designed three constructs to display the G central conserved domain (Gcc) focused on inducing broad and potent neutralizing antibodies. One construct displaying Gcc from both RSV subgroups trimerized via a C-terminal foldon (Gcc-Foldon) was highly immunogenic in mice and in MIMIC, a pre-immune human in vitro model. To explore an optimal RSV vaccine, we combined the Gcc-Foldon antigen with a stabilized pre-fusion-F nanoparticle (pre-F-NP) as a bivalent vaccine and detected no antigenic interference between the two antigens in the MIMIC model. In RSV-primed macaques, the bivalent vaccine elicited potent humoral responses. Furthermore, both Gcc-Foldon and the bivalent vaccine conferred effective protection against RSV challenge in mice. This two-component vaccine could potentially provide effective protection against RSV infection in humans and warrants further clinical evaluation. [ABSTRACT FROM AUTHOR]

Herpes zoster (HZ) is caused by reactivation of latent varicella-zoster virus (VZV) when VZV-specific cellular immunity is insufficient to control reactivation. Currently, Shingrix, which contains the VZV gE protein and GSK's AS01B adjuvant composed of liposomes formulated with cholesterol, monophosphoryl lipid A (MPL) and QS21, is used for prevention of HZ. However, reactogenicity to Shingrix is common leading to poor patient compliance in receiving one or both shots. Here, we evaluated the immunogenicity of a newly formulated gE protein-based HZ vaccine containing Second-generation Lipid Adjuvant (SLA), a synthetic TLR4 ligand, formulated in an oil-in-water emulsion (SLA-SE) without QS21 (gE/SLA-SE). In VZV-primed mouse models, gE/SLA-SE-induced gE-specific humoral and cellular immune responses at comparable levels to those elicited by Shingrix in young mice, as both gE/SLA-SE and Shingrix induce polyfunctional CD4+ T-cell responses. In aged mice, gE/SLA-SE elicited more robust gE-specific T-cell responses than Shingrix. Furthermore, gE/SLA-SE-induced T-cell responses were sustained until 5 months after immunization. Thus, QS21-free, gE/SLA-SE is a promising candidate for development of gE-based HZ vaccines with high immunogenicity—particularly when targeting an older population. [ABSTRACT FROM AUTHOR]

We recently reported a lack of interference between inactivated rotavirus vaccine (IRV) and inactivated poliovirus vaccine (IPV) and their potential dose sparing when the two vaccines were administered intramuscularly either in combination or standalone in rats and guinea pigs. In the present study, we optimized the formulations of both vaccines and investigated the feasibility of manufacturing a combined IRV-IPV dissolving microneedle patch (dMNP), assessing its compatibility and immunogenicity in rats. Our results showed that IRV delivered by dMNP alone or in combination with IPV induced similar levels of RV-specific IgG and neutralizing antibody. Likewise, IPV delivered by dMNP alone or in combination with IRV induced comparable levels of neutralizing antibody of poliovirus types 1, 2, and 3. We further demonstrated high stability of IRV-dMNP at 5, 25, and 40 °C and IPV-dMNP at 5 and 25 °C, and found that three doses of IRV or IPV when co-administered at a quarter dose was as potent as a full target dose in inducing neutralizing antibodies against corresponding rotavirus or poliovirus. We conclude that IRV-IPV dMNP did not interfere with each other in triggering an immunologic response and were highly immunogenic in rats. Our findings support the further development of this innovative approach to deliver a novel combination vaccine against rotavirus and poliovirus in children throughout the world. [ABSTRACT FROM AUTHOR]

Soluble HIV-1 envelope glycoprotein (Env) immunogens are a prime constituent of candidate vaccines designed to induce broadly neutralizing antibodies. Several lines of evidence suggest that enhancing Env immunogen thermostability can improve neutralizing antibody (NAb) responses. Here, we generated BG505 SOSIP.v9 trimers, which displayed virtually no reactivity with non-neutralizing antibodies and showed increased global and epitope thermostability, compared to previous BG505 SOSIP versions. Chemical crosslinking of BG505 SOSIP.v9 further increased the melting temperature to 91.3 °C, which is almost 25 °C higher than that of the prototype SOSIP.664 trimer. Next, we compared the immunogenicity of a palette of BG505-based SOSIP trimers with a gradient of thermostabilities in rabbits. We also included SOSIP.v9 proteins in which a strain-specific immunodominant epitope was masked by glycans to redirect the NAb response to other subdominant epitopes. We found that increased trimer thermostability correlated with increased potency and consistency of the autologous NAb response. Furthermore, glycan masking steered the NAb response to subdominant epitopes without decreasing the potency of the autologous NAb response. In summary, SOSIP.v9 trimers and their glycan masked versions represent an improved platform for HIV-1 Env based vaccination strategies. [ABSTRACT FROM AUTHOR]

Vaccination with typhoid conjugate vaccines (TCV) is a major part of typhoid prevention. However, little is known about long-term immune persistence following vaccination with TCVs. In this phase-2, randomized double-blind trial (NCT03527355), 285 children aged 6–23 months were randomized to one of three groups: (1) the group that received a first dose of Vi polysaccharide conjugated to diphtheria-toxoid (Vi-DT) vaccine followed by an "early booster" at 24 weeks, (2) the group that which received a first dose of Vi-DT followed by a "late booster" at 96 or 110 weeks, and (3) comparator group. Safety and immunogenicity of anti-Vi IgG GMTs were assessed at weeks 0, 4, 24, 28, 60, 96, 110, and 114 since the first dose. Here, we describe persistence of immune responses at weeks 60, 96, 110, and 114 post first dose. The anti-Vi IgG seroconversion rate after 27.5 months of follow-up was 88.16% (95% CI: 79.00, 93.64) in late-booster and 94.76% (95% CI: 86.91, 97.88) in early booster Vi-DT groups (p = 0.081). Whereas anti-Vi IgG GMTs were significantly higher in the early booster group (11.95 [95% CI: 9.65, 14.81]) than prebooster GMTs in the late booster group (5.50 [95% CI: 4.44, 6.80], p < 0.0001). GMT in the late booster group significantly increased to 351.76 (95% CI: 265.01, 466.93) (p < 0.0001) when measured 4 weeks after they received their "late-booster" shot. In conclusion, late booster dosing with Vi-DT at 27.5 months post first dose was safe and elicited robust anti-Vi IgG immune responses. Anti-Vi IgG seroconversion rates were persistently comparable in early and late-booster Vi-DT groups. [ABSTRACT FROM AUTHOR]

Two phase 3 clinical studies were conducted in the USA to bridge across different Ad26.ZEBOV manufacturing processes and sites, and to evaluate the immunogenicity of different dose levels of Ad26.ZEBOV and MVA-BN-Filo. Study 1 evaluated the immunological equivalence of three batches of Ad26.ZEBOV administered as dose 1, followed by one batch of MVA-BN-Filo as dose 2. In Study 2, immunogenic non-inferiority of intermediate (Ad26.ZEBOV: 2 × 1010 viral particles [vp], MVA-BN-Filo: 5 × 107 infectious units [Inf.U]) and low (8 × 109 vp, 5 × 107 Inf.U) doses of Ad26.ZEBOV and MVA-BN-Filo were evaluated against the full clinical dose (5 × 1010 vp, 1 × 108 Inf.U). In Study 1, equivalence was demonstrated for two of three batch comparisons post-dose 1 and all three batches after the full regimen. Study 2 demonstrated a dose-dependent response; however, non-inferiority against the full clinical dose was not met. All regimens were well tolerated and immune responses were observed in all participants, regardless of manufacturing process or dose. Consistency of immunogenicity of different Ad26.ZEBOV batches was demonstrated and a dose-dependent response was observed after Ad26.ZEBOV, MVA-BN-Filo vaccination. ClinicalTrials.gov identifiers: NCT02543268; NCT02543567. [ABSTRACT FROM AUTHOR]

Japanese encephalitis virus (JEV) is the etiological agent of Japanese encephalitis (JE). The most commonly used vaccine used to prevent JE is the live-attenuated strain SA14-14-2, which was generated by serial passage of the wild-type (WT) JEV strain SA14. Two other vaccine candidates, SA14-5-3 and SA14-2-8 were derived from SA14. Both were shown to be attenuated but lacked sufficient immunogenicity to be considered effective vaccines. To better contrast the SA14-14-2 vaccine with its less-immunogenic counterparts, genetic diversity, ribavirin sensitivity, mouse virulence and mouse immunogenicity of the three vaccines were investigated. Next generation sequencing demonstrated that SA14-14-2 was significantly more diverse than both SA14-5-3 and SA14-2-8, and was slightly less diverse than WT SA14. Notably, WT SA14 had unpredictable levels of diversity across its genome whereas SA14-14-2 is highly diverse, but genetic diversity is not random, rather the virus only tolerates variability at certain residues. Using Ribavirin sensitivity in vitro, it was found that SA14-14-2 has a lower fidelity replication complex compared to SA14-5-3 and SA14-2-8. Mouse virulence studies showed that SA14-2-8 was the most virulent of the three vaccine strains while SA14-14-2 had the most favorable combination of safety (virulence) and immunogenicity for all vaccines tested. SA14-14-2 contains genetic diversity and sensitivity to the antiviral Ribavirin similar to WT parent SA14, and this genetic diversity likely explains the (1) differences in genomic sequences reported for SA14-14-2 and (2) the encoding of major attenuation determinants by the viral E protein. [ABSTRACT FROM AUTHOR]

Activation of antigen-specific T-lymphocyte responses may be needed to cure disorders caused by chronic infection with low-risk human papillomavirus (lrHPV). Safe and effective adjuvant therapies for such disorders are needed. The safety and efficacy of a novel gorilla adenovirus vaccine expressing a protein designed to elicit immune responses directed against HPV6 and HPV11, PRGN-2012, was studied using in vitro stimulation of T lymphocytes from patients with recurrent respiratory papillomatosis, in vivo vaccination studies, and therapeutic studies in mice bearing tumors expressing lrHPV antigen. PRGN-2012 treatment induces lrHPV antigen-specific responses in patient T lymphocytes. Vaccination of wild-type mice induces E6-specific T-lymphocyte responses without toxicity. In vivo therapeutic vaccination of mice bearing established HPV6 E6 expressing tumors results in HPV6 E6-specific CD8+ T-lymphocyte immunity of sufficient magnitude to induce tumor growth delay. The clinical study of PRGN-2012 in patients with disorders caused by chronic infection with lrHPV is warranted. [ABSTRACT FROM AUTHOR]

Plasmodium falciparum apical membrane antigen 1 (PfAMA1) is a candidate malaria vaccine antigen expressed on merozoites and sporozoites. PfAMA1's polymorphic nature impacts vaccine-induced protection. To address polymorphism, three Diversity Covering (DiCo) protein sequences were designed and tested in a staggered phase Ia/b trial. A cohort of malaria-naive adults received PfAMA1-DiCo adjuvanted with Alhydrogel® or GLA-SE and a cohort of malaria-exposed adults received placebo or GLA-SE adjuvanted PfAMA1 DiCo at weeks 0, 4 and 26. IgG and GIA levels measured 4 weeks after the third vaccination are similar in malaria-naive volunteers and placebo-immunised malaria-exposed adults, and have a similar breadth. Vaccination of malaria-exposed adults results in significant antibody level increases to the DiCo variants, but not to naturally occurring PfAMA1 variants. Moreover, GIA levels do not increase following vaccination. Future research will need to focus on stronger adjuvants and/or adapted vaccination regimens, to induce potentially protective responses in the target group of the vaccine. [ABSTRACT FROM AUTHOR]

Live attenuated influenza vaccine (LAIV) is widely used to protect humans from seasonal influenza infection, particularly in children. In contrast to inactivated vaccines, the LAIV can induce both mucosal and cellular immune responses. Here we show that a single dose of monovalent H1N1pdm09-specific LAIV in the ferret model is fully protective against a subsequent wild-type H1N1pdm09 challenge, and furthermore reduces the severity of disease following challenge with a different influenza A subtype (H3N2). The reduced severity comprised reductions in weight loss and fever, as well as more rapid clearance of virus, compared to non-vaccinated H3N2-challenged ferrets. No H3N2-neutralizing antibodies were detected in vaccinated ferret sera. Rather, heterosubtypic protection correlated with interferon-gamma+ (IFN-γ+) T-cell responses measured in peripheral blood and in lung lymphocytes. The IFN-γ+ cells were cross-reactive to H3N2 virus even when obtained from vaccinated animals that had never been exposed to H3N2 virus. We believe this study provides compelling evidence that the LAIV can provide a significant reduction in infection and symptoms when challenged with heterosubtypic influenza strains not included in the LAIV, highlighting the importance of cross-reactive T-cells in the design of a universal influenza vaccine. [ABSTRACT FROM AUTHOR]

Lassa virus (LASV) infects hundreds of thousands of individuals each year, highlighting the need for the accelerated development of preventive, diagnostic, and therapeutic interventions. To date, no vaccine has been licensed for LASV. ChAdOx1-Lassa-GPC is a chimpanzee adenovirus-vectored vaccine encoding the Josiah strain LASV glycoprotein precursor (GPC) gene. In the following study, we show that ChAdOx1-Lassa-GPC is immunogenic, inducing robust T-cell and antibody responses in mice. Furthermore, a single dose of ChAdOx1-Lassa-GPC fully protects Hartley guinea pigs against morbidity and mortality following lethal challenge with a guinea pig-adapted LASV (strain Josiah). By contrast, control vaccinated animals reached euthanasia criteria 10–12 days after infection. Limited amounts of LASV RNA were detected in the tissues of vaccinated animals. Viable LASV was detected in only one animal receiving a single dose of the vaccine. A prime-boost regimen of ChAdOx1-Lassa-GPC in guinea pigs significantly increased antigen-specific antibody titers and cleared viable LASV from the tissues. These data support further development of ChAdOx1-Lassa-GPC and testing in non-human primate models of infection. [ABSTRACT FROM AUTHOR]

Although live attenuated vaccines (LAVs) have been effective in the control of flavivirus infections, to date they have been excluded from Zika virus (ZIKV) vaccine trials due to safety concerns. We have previously reported two ZIKV mutants, each of which has a single substitution in either envelope (E) glycosylation or nonstructural (NS) 4B P36 and displays a modest reduction in mouse neurovirulence and neuroinvasiveness, respectively. Here, we generated a ZIKV mutant, ZE4B-36, which combines mutations in both E glycosylation and NS4B P36. The ZE4B-36 mutant is stable and attenuated in viral replication. Next-generation sequence analysis showed that the attenuating mutations in the E and NS4B proteins are retained during serial cell culture passages. The mutant exhibits a significant reduction in neuroinvasiveness and neurovirulence and low infectivity in mosquitoes. It induces robust ZIKV-specific memory B cell, antibody, and T cell-mediated immune responses in type I interferon receptor (IFNR) deficient mice. ZIKV-specific T cell immunity remains strong months post-vaccination in wild-type C57BL/6 (B6) mice. Vaccination with ZE4B-36 protects mice from ZIKV-induced diseases and vertical transmission. Our results suggest that combination mutations in E glycosylation and NS4B P36 contribute to a candidate LAV with significantly increased safety but retain strong immunogenicity for prevention and control of ZIKV infection. [ABSTRACT FROM AUTHOR]

This study tests the hypothesis that an Onchocerca volvulus vaccine, consisting of two recombinant antigens (Ov-103 and Ov-RAL-2) formulated with the combination-adjuvant Advax-2, can induce protective immunity in genetically diverse Collaborative Cross recombinant inbred intercross mice (CC-RIX). CC-RIX lines were immunized with the O. volvulus vaccine and challenged with third-stage larvae. Equal and significant reductions in parasite survival were observed in 7 of 8 CC-RIX lines. Innate protective immunity was seen in the single CC-RIX line that did not demonstrate protective adaptive immunity. Analysis of a wide array of immune factors showed that each line of mice have a unique set of immune responses to vaccination and challenge suggesting that the vaccine is polyfunctional, inducing different equally-protective sets of immune responses based on the genetic background of the immunized host. Vaccine efficacy in genetically diverse mice suggests that it will also be effective in genetically complex human populations. [ABSTRACT FROM AUTHOR]

Personalized cancer vaccines targeting neoantigens arising from somatic missense mutations are currently being evaluated for the treatment of various cancers due to their potential to elicit a multivalent, tumor-specific immune response. Several cancers express a low number of neoantigens; in these cases, ensuring the immunotherapeutic potential of each neoantigen-derived epitope (neoepitope) is crucial. In this study, we discovered that therapeutic vaccines targeting immunodominant major histocompatibility complex (MHC) I-restricted neoepitopes require a conjoined helper epitope in order to induce a cytotoxic, neoepitope-specific CD8+ T-cell response. Furthermore, we show that the universally immunogenic helper epitope P30 can fulfill this requisite helper function. Remarkably, conjoined P30 was able to unveil immune and antitumor responses to subdominant MHC I-restricted neoepitopes that were, otherwise, poorly immunogenic. Together, these data provide key insights into effective neoantigen vaccine design and demonstrate a translatable strategy using a universal helper epitope that can improve therapeutic responses to MHC I-restricted neoepitopes. [ABSTRACT FROM AUTHOR]

Malaria remains a major cause of morbidity and mortality worldwide with 219 million infections and 435,000 deaths predominantly in Africa. The infective Plasmodium sporozoite is the target of a potent humoral immune response that can protect murine, simian and human hosts against challenge by malaria-infected mosquitoes. Early murine studies demonstrated that sporozoites or subunit vaccines based on the sporozoite major surface antigen, the circumsporozoite (CS) protein, elicit antibodies that primarily target the central repeat region of the CS protein. In the current murine studies, using monoclonal antibodies and polyclonal sera obtained following immunization with P. falciparum sporozoites or synthetic repeat peptides, we demonstrate differences in the ability of these antibodies to recognize the major and minor repeats contained in the central repeat region. The biological relevance of these differences in fine specificity was explored using a transgenic P. berghei rodent parasite expressing the P. falciparum CS repeat region. In these in vitro and in vivo studies, we demonstrate that the minor repeat region, comprised of three copies of alternating NANP and NVDP tetramer repeats, contains an epitope recognized by sporozoite-neutralizing antibodies. In contrast, murine monoclonal antibodies specific for the major CS repeats (NANP)n could be isolated from peptide-immunized mice that had limited or no sporozoite-neutralizing activity. These studies highlight the importance of assessing the fine specificity and functions of antirepeat antibodies elicited by P. falciparum CS-based vaccines and suggest that the design of immunogens to increase antibody responses to minor CS repeats may enhance vaccine efficacy. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus represents a serious infectious threat to global public health and a vaccine against S. aureus represents an unmet medical need. We here characterise two S. aureus vaccine candidates, coproporphyrinogen III oxidase (CgoX) and triose phosphate isomerase (TPI), which fulfil essential housekeeping functions in heme synthesis and glycolysis, respectively. Immunisation with rCgoX and rTPI elicited protective immunity against S. aureus bacteremia. Two monoclonal antibodies (mAb), CgoX-D3 and TPI-H8, raised against CgoX and TPI, efficiently provided protection against S. aureus infection. MAb-CgoX-D3 recognised a linear epitope spanning 12 amino acids (aa), whereas TPI-H8 recognised a larger discontinuous epitope. The CgoX-D3 epitope conjugated to BSA elicited a strong, protective immune response against S. aureus infection. The CgoX-D3 epitope is highly conserved in clinical S. aureus isolates, indicating its potential wide usability against S. aureus infection. These data suggest that immunofocusing through epitope-based immunisation constitutes a strategy for the development of a S. aureus vaccine with greater efficacy and better safety profile. [ABSTRACT FROM AUTHOR]

Obesity and cirrhosis are associated with poor hepatitis B virus (HBV) vaccine responses, but vaccine efficacy has not been assessed in nonalcoholic fatty liver disease (NAFLD). Sixty-eight HBV-naïve adults with NAFLD were enrolled through the Canadian HBV network and completed three-dose HBV or HBV/HAV vaccine (Engerix-B®, or Twinrix®, GlaxoSmithKline). Anti-HBs titers were measured at 1–3 months post third dose. In 31/68 subjects enrolled at the coordinating-site, T-cell proliferation and follicular T-helper cells (pTFH) were assessed using PBMC. Immune response was also studied in NAFLD mice. NAFLD patients were stratified as low-risk-obesity, BMI < 35 (N = 40) vs. medium-high-risk obesity, BMI > 35 (N = 28). Anti-HBs titers were lower in medium/high-risk obesity, 385 IU/L ± 79 vs. low-risk obesity class, 642 IU/L ± 68.2, p = 0.02. High-risk obesity cases, N = 14 showed lower vaccine-specific-CD3+ CD4+ T-cell response compared to low-risk obesity patients, N = 17, p = 0.02. Low vaccine responders showed dysfunctional pTFH. NAFLD mice showed lower anti-HBs levels and T-cell response vs. controls. In conclusion, we report here that obese individuals with NAFLD exhibit decreased HBV vaccine-specific immune responses. [ABSTRACT FROM AUTHOR]

A single intradermal vaccination with MTBVAC given to adult rhesus macaques was well tolerated and conferred a significant improvement in outcome following aerosol exposure to M. tuberculosis compared to that provided by a single BCG vaccination. Vaccination with MTBVAC resulted in a significant reduction in M. tuberculosis infection-induced disease pathology measured using in vivo medical imaging, in gross pathology lesion counts and pathology scores recorded at necropsy, the frequency and severity of pulmonary granulomas and the frequency of recovery of viable M. tuberculosis from extrapulmonary tissues following challenge. The immune profiles induced following immunisation with MTBVAC reflect those identified in human clinical trials of MTBVAC. Evaluation of MTBVAC- and TB peptide-pool-specific T-cell cytokine production revealed a predominantly Th1 response from poly- (IFN-γ+TNF-α+IL2+) and multi-(IFN-γ+TNF-α+) functional CD4 T cells, while only low levels of Th22, Th17 and cytokine-producing CD8 T-cell populations were detected together with low-level, but significant, increases in CFP10-specific IFN-γ secreting cells. In this report, we describe concordance between immune profiles measured in clinical trials and a macaque pre-clinical study demonstrating significantly improved outcome after M. tuberculosis challenge as evidence to support the continued development of MTBVAC as an effective prophylactic vaccine for TB vaccination campaigns. [ABSTRACT FROM AUTHOR]

We present a non-human primate mycobacterial growth inhibition assay (MGIA) using in vitro blood or cell co-culture with the aim of refining and expediting early tuberculosis vaccine testing. We have taken steps to optimise the assay using cryopreserved peripheral blood mononuclear cells, transfer it to end-user institutes, and assess technical and biological validity. Increasing cell concentration or mycobacterial input and co-culturing in static 48-well plates compared with rotating tubes improved intra-assay repeatability and sensitivity. Standardisation and harmonisation efforts resulted in high consistency agreements, with repeatability and intermediate precision <10% coefficient of variation (CV) and inter-site reproducibility <20% CV; although some systematic differences were observed. As proof-of-concept, we demonstrated ability to detect a BCG vaccine-induced improvement in growth inhibition in macaque samples, and a correlation between MGIA outcome and measures of protection from in vivo disease development following challenge with either intradermal BCG or aerosol/endobronchial Mycobacterium tuberculosis (M.tb) at a group and individual animal level. [ABSTRACT FROM AUTHOR]