NPJ Vaccines最新文献

After the COVID-19 pandemic, significant increases in measles cases were observed globally. Community-wide vaccination remains the most effective strategy for preventing measles. However, it is crucial to understand whether prevalent genotypes, when circulating in populations with suboptimal vaccination coverage, may undergo adaptive mutations that allow them to escape vaccine-induced immunity. In this study, a bioinformatics-guided approach was used to predict universal helper T-cell epitopes specific to the measles vaccine virus (vaccine-MeV) presented by multiple HLA-DR, -DP, and -DQ alleles to achieve population-wide coverage. By using MeV-specific T-cell lines, we identified 37 functional epitopes out of 83 predicted candidates, including 25 novel ones. Strikingly, 73% of these epitope regions were associated with sequence variations in wild-type viruses. More importantly, we demonstrated that mutations disrupted the ability of vaccine-induced CD4⁺ T cells to respond to circulating viruses. Consequently, mutations in epitope regions of circulating viruses may affect the effectiveness of vaccine-induced T-cell immunity.

Malaria resurgence in 2022 saw 249 million clinical cases and 608,000 deaths, mostly in children under five. The WHO-approved circumsporozoite protein (CSP)-targeting vaccines, RTS,S and R21, remain limited in availability. Strong humoral responses are crucial for sporozoite neutralization before hepatocyte infection, yet first-generation vaccines provide suboptimal protection, necessitating improved strategies. With the success of mRNA-LNP vaccines against COVID-19, there is interest in leveraging this approach to malaria. Here, we developed a novel chemokine fusion mRNA vaccine targeting immature dendritic cells (iDC) to enhance immunity against P. falciparum CSP (PfCSP). Mice immunized with MIP3α-CSP mRNA-LNP exhibited stronger CD4 + T cell responses and higher anti-NANP6 antibody titers than conventional CSP mRNA-LNP. Importantly, upon P. berghei PfCSP transgenic sporozoite challenge, MIP3α-CSP mRNA provided significantly greater protection from liver infection, strongly associated with multifunctional CD4 + T cells and anti-NANP6 titers. This study underscores iDC targeting as a promising strategy to enhance malaria vaccine efficacy.

Opioid overdose deaths are an evolving public health emergency in the United States. Recent advancements in drug conjugate vaccine design and adjuvantation technologies have re-ignited interest in the potential clinical utility of opioid vaccination. Here we present the concept of fentanyl vaccination as a complementary strategy for opioid overdose prevention with a focus on vaccine safety, efficacy, and considerations for vaccine development and testing in early phase human clinical trials.

We report a comprehensive evaluation of the toxin B (TcdB) vaccine adjuvanted with a dual Toll-like receptor ligand liposome adjuvant for Clostridioides difficile infection (CDI). The vaccine completely protected mice from a lethal infection. Compared to alum adjuvanted TcdB, it generated functionally superior systemic antibodies and supported strong memory B cell and gut IgA responses. This pharmaceutically acceptable adjuvant platform holds promise for developing a next-generation CDI vaccine.

Influenza virus nucleoprotein (NP) is a promising target for universal influenza vaccines due to its conservation and high immunogenicity. Here, we uncovered a previously unknown factor that E. coli-produced NP carries bacterial RNA, which is crucial for its high immunogenicity but may pose safety and consistency concerns due to batch variability. To address these concerns, we developed a NP mutant (NP_mut) that lacks RNA binding activity but can be loaded with CpG1826, a synthetic oligodeoxynucleotide adjuvant that has been used in the FDA-approved Hepatitis B vaccine. The CpG1826-loaded NP_mut induced immune responses comparable to RNA-bound NP while eliminating safety risks. Additionally, the mixture of CpG1826-loaded NP_mut and 3M2e protein (three tandem copies of the ectodomain of influenza M2 protein) provided enhanced protection against influenza viruses challenge. Our findings highlight the adjuvant activity of bacterial RNA in E. coli-produced NP and propose a safer strategy for developing universal influenza vaccines.

Dogs are the main reservoir host of Leishmania infantum, etiological agent of zoonotic visceral leishmaniasis (ZVL). An effective vaccine against Canine Visceral Leishmaniasis (CVL) will help the control and elimination of ZVL. In this study, we evaluated in dogs the safety, immunogenicity, and efficacy of a live attenuated Leishmania major Centrin gene-deleted (LmCen^-/-) as a vaccine. Two doses (10⁶ or 10⁷) of LmCen^-/- vaccine were administered intradermally in a prime-boost regimen. Both vaccine doses induced equally high level of IgG anti-Leishmania and exhibited strong antigen-specific cellular responses with IFN-γ production by CD4 + T cells one-month post-immunization. A second cohort of dogs was vaccinated with 10⁶ LmCen^-/- parasites one month prior to their transfer to a CVL endemic focus in Northern Tunisia for exposure to sand fly bites during three successive transmission seasons. Dogs were exposed to bite from naturally infected sandflies for 3-5 months per year. Our results showed that only 1/11 vaccinated dogs became PCR positive for Leishmania and developed clinical signs of CVL. In contrast, 4/11 unvaccinated dogs were tested PCR positive for Leishmania and displayed oligosymptomatic CVL, demonstrating that immunization with LmCen^-/- vaccine confers long-term protection with an efficacy of 82.5% against CVL in natural transmission settings.

Vaccines against SARS-CoV-2 have targeted the spike protein and have been successful at preventing disease. However, with the emergence of variants, spike-specific vaccines become less effective. The nucleocapsid protein is relatively conserved among variants of SARS-CoV-2 and is a candidate for addition to spike in next generation vaccines for the induction of T cell protection. Previous studies on SARS-CoV have suggested that the induction of an immune response to nucleocapsid could result in enhanced disease. Using the K18-hACE2 mouse model we investigated immunization with a variant nucleocapsid, from SARS CoV (N1) alone or in combination with spike from SARS-CoV-2 and compared this to nucleocapsid from SARS-CoV-2 (N2). The spike-nucleocapsid-based vaccines conferred protection against SARS-CoV-2 in lungs and brain and decreased lung pathology compared to control mice. However, higher T and B cell immune responses were observed in N1-immunized mice prior to challenge, whether delivered alone or with spike, and immunization with N1 resulted in increased lung pathology compared to immunization with spike or N2. These findings suggest that spike-nucleocapsid-based vaccines are safe and effective, even with variant nucleocapsid sequences, but that viral control in this mouse model may be associated with higher lung pathology, compared to spike immunization alone, due to the immunogenic qualities of the nucleocapsid antigen.

Vaccine hesitancy seriously compromised the COVID-19 vaccine roll-out across the Western Pacific with limited evidence-based recommendations for diverse populations across the region. This study investigates the profile of the vaccine-hesitant populations by using fixed-effect latent class analysis and multi-country survey data collected in 12 countries in 2021 and 2022: Cambodia, Viet Nam, Lao PDR, Japan, Republic of Korea, Malaysia, Philippines, Mongolia, Fiji, Solomon Islands, Tonga and Vanuatu. The analysis identified 9 latent classes: Stay-at-home mothers, High-school-educated employees, High-school-educated older adults, High-school-educated young adults, University-educated employees, University-educated older adults, University-educated young adults, Unemployed, Non-compliant employees. The probabilities of COVID-19 vaccine acceptance and booster uptake were significantly lower in most of these latent classes, compared to University-educated older adults, as the reference group. While each country had unique compositions of latent classes among vaccine-hesitant people, there were also some shared risk groups, such as High-school-educated employees and High-school-educated young adults, across the countries. The study findings demonstrate the benefits of subgroup analysis in unpacking the complex interplay of characteristics within vaccine-hesitant populations, highlighting the need for customised strategies tailored to each country's unique profile of vaccine hesitancy.

Adjuvants play a crucial role in enhancing vaccine efficacy. Although several adjuvants have been approved, there remains a demand for safer and more effective adjuvants for nasal vaccines. Here, we identified calboxyvinyl polymer (CVP) as a superior mucosal vaccine adjuvant from pharmaceutical base materials using our screening systems; single nasal vaccination of the CVP-combined influenza split vaccine-induced antigen-specific IgA and IgG antibodies and provided protection against lethal influenza virus infection. Furthermore, nasal vaccination with CVP-combined severe acute respiratory syndrome coronavirus 2 antigen protected against the virus and stimulated the production of highly cross-reactive IgG antibodies against variants XBB1.5 and JN.1. Intriguingly, intramuscular vaccination of the CVP-combined vaccine also elicited the production of IgA antibodies in both nasal wash and bronchoalveolar lavage fluid in mice and cynomolgus monkeys. CVP therefore offers superior adjuvanticity to existing adjuvants and is anticipated to be a safe and effective adjuvant for mucosal vaccines.

The pivotal role of type 1 conventional dendritic cells (cDC1s) in the field of dendritic cell (DC)-based tumor immunotherapies has been gaining increasing recognition due to their superior antigen cross-presentation abilities and essential role in modulating immune responses. This review specifically highlights the C-type lectin receptor family 9 member A (Clec9a or DNGR-1), which is exclusively expressed on cDC1s and plays a pivotal role in augmenting antigen cross-presentation and cytotoxic T lymphocyte (CTL) responses while simultaneously mitigating off-target effects. These effects include the enhancement of the cDC1s cross-presentation, reducing autoimmune responses and systemic inflammation, as well as preventing the non-specific activation of other immune cells. Consequently, these actions may contribute to reduced toxicity and enhanced treatment efficacy in immunotherapy. The exceptional ability of Clec9a to cross-present dead cell-associated antigens and enhance both humoral and CTL responses makes it an optimal receptor for DC-based strategies aimed at strengthening antitumor immunity. This review provides a comprehensive overview of the molecular characterization, expression, and signaling mechanisms of Clec9a. Furthermore, it discusses the role of Clec9a in the induction and functional activation of Clec9a⁺ cDC1s, with a particular focus on addressing the challenges related to off-target effects and immune tolerance in the development of tumor vaccines. Additionally, this review explores the potential of Clec9a-targeted approaches to enhance the immunogenicity of tumor vaccines and addresses the utilization of Clec9a as a delivery target for specific agonists (such as STING agonists and αGC) to enhance their therapeutic effects. This novel approach leverages Clec9a's capacity to improve the precision and efficacy of these immunomodulatory molecules in tumor treatment. In summary, this review presents compelling evidence positioning Clec9a as a promising target for DC-based tumor immunotherapy, capable of enhancing the efficacy of vaccines and immune responses while minimizing adverse effects.