Rational Vaccine Design Research Articles

Conformation-Stabilized Amorphous Nanocoating for Rational Design of Long-Term Thermostable Viral Vaccines.

Despite the great potency of vaccines to combat infectious diseases, their global use is hindered by a lack of thermostability, which leads to a constant need for cold-chain storage. Here, aiming at long-term thermostability and eliminating cold-chain requirements of bioactive vaccines, we propose that efforts should focus on tailoring the conformational stability of vaccines. Accordingly, we design a nanocoating composed of histidine (His)-coordinated amorphous Zn and 2-methylimidazolate complex (His-aZn-mIM) on single nanoparticles of viral vaccines to introduce intramolecular coordinated linkage between viruses and the nanocoatings. The coordinated nanocoating enhances the rigidity of proteins and preserves the vaccine's activity. Importantly, integrating His into the original Zn-N coordinative environment symbiotically reinforces its tolerance to biological and hydrothermal solutions, resulting in the augmented thermostability following the Hofmeister effect. Thus, even after storage of His-aZn-mIM encapsulated Human adenovirus type 5 (Ad5@His-aZn-mIM) at 25 °C for 90 d, the potency loss of the coated Ad5 is less than 10%, while the native Ad5 becomes 100% ineffective within one month. Such a nanocoating gains thermostability by forming an ultrastable hydration shell, which prevents viral proteins from unfolding under the attack of hydration ions, providing a conformational stabilizer upon heat exposure. Our findings represent an easy-access biomimetic platform to address the long-term vaccine storage without the requirement of a cold chain.

The role of antigen expression in shaping the repertoire of HLA presented ligands

SummaryHuman leukocyte antigen (HLA) presentation of peptides is a prerequisite of T cell immune activation. The understanding of the rules defining this event has large implications for our knowledge of basic immunology and for the rational design of immuno-therapeutics and vaccines. Historically, most of the available prediction methods have been solely focused on the information related to antigen processing and presentation. Recent work has, however, demonstrated that method performance can be boosted by integrating information related to antigen abundance. Here we expand on these later findings and develop an extended version of NetMHCpan, called NetMHCpanExp, integrating information on antigen abundance from RNA-Seq experiments. In line with earlier works, the model demonstrates improved performance for both HLA ligand and cancer neoantigen epitope prediction. Optimal results are obtained by use of sample-specific abundance information but also reference datasets can be applied with a limited performance drop. The developed tool is available at https://services.healthtech.dtu.dk/service.php?NetMHCpanExp-1.0.

The next frontier in vaccine design: blending immune correlates of protection into rational vaccine design.

Despite the extraordinary speed and success in SARS-Cov-2 vaccine development, the emergence of variants of concern perplexed the vaccine development community. Neutralizing antibodies waned antibodies waned and were evaded by viral variants, despite the preservation of protection against severe disease and death across vaccinated populations. Similar to other vaccine design efforts, the lack of mechanistic correlates of immunity against Coronavirus Disease 2019, raised questions related to the need for vaccine redesign and boosting. Hence, our limited understanding of mechanistic correlates of immunity – across pathogens - remains a major obstacle in vaccine development. The identification and incorporation of mechanistic correlates of immunity are key to the accelerated design of highly impactful globally relevant vaccines. Systems-biology tools can be applied strategically to define a complete understanding of mechanistic correlates of immunity. Embedding immunological dissection and target immune profile identification, beyond canonical antibody binding and neutralization, may accelerate the design and success of durable protective vaccines.

Broadly neutralizing antibodies to SARS-related viruses can be readily induced in rhesus macaques.

To prepare for future coronavirus (CoV) pandemics, it is desirable to generate vaccines capable of eliciting broadly neutralizing antibody responses to CoVs. Here, we show that immunization of macaques with SARS-CoV-2 spike (S) protein with a two-shot protocol generated potent serum receptor binding domain cross-neutralizing antibody responses to both SARS-CoV-2 and SARS-CoV-1. Furthermore, responses were equally effective against most SARS-CoV-2 variants of concern (VOCs) and some were highly effective against Omicron. This result contrasts with human infection or many two-shot vaccination protocols where responses were typically more SARS-CoV-2 specific and where VOCs were less well neutralized. Structural studies showed that cloned macaque neutralizing antibodies, particularly using a given heavy chain germline gene, recognized a relatively conserved region proximal to the angiotensin converting enzyme 2 receptor binding site (RBS), whereas many frequently elicited human neutralizing antibodies targeted more variable epitopes overlapping the RBS. B cell repertoire differences between humans and macaques appeared to influence the vaccine response. The macaque neutralizing antibodies identified a pan-SARS-related virus epitope region less well targeted by human antibodies that could be exploited in rational vaccine design.

Vaccine adjuvants to engage the cross-presentation pathway.

Adjuvants are indispensable components of vaccines for stimulating optimal immune responses to non-replicating, inactivated and subunit antigens. Eliciting balanced humoral and T cell-mediated immunity is paramount to defend against diseases caused by complex intracellular pathogens, such as tuberculosis, malaria, and AIDS. However, currently used vaccines elicit strong antibody responses, but poorly stimulate CD8 cytotoxic T lymphocyte (CTL) responses. To elicit potent CTL memory, vaccines need to engage the cross-presentation pathway, and this requirement has been a crucial bottleneck in the development of subunit vaccines that engender effective T cell immunity. In this review, we focus on recent insights into DC cross-presentation and the extent to which clinically relevant vaccine adjuvants, such as aluminum-based nanoparticles, water-in oil emulsion (MF59) adjuvants, saponin-based adjuvants, and Toll-like receptor (TLR) ligands modulate DC cross-presentation efficiency. Further, we discuss the feasibility of using carbomer-based adjuvants as next generation of adjuvant platforms to elicit balanced antibody- and T-cell based immunity. Understanding of the molecular mechanism of DC cross-presentation and the mode of action of adjuvants will pave the way for rational design of vaccines for infectious diseases and cancer that require balanced antibody- and T cell-based immunity.

The Relative Positioning of B and T Cell Epitopes Drives Immunodominance.

Humoral immunity is crucial for protection against invading pathogens. Broadly neutralizing antibodies (bnAbs) provide sterilizing immunity by targeting conserved regions of viral variants and represent the goal of most vaccination approaches. While antibodies can be selected to bind virtually any region of a given antigen, the consistent induction of bnAbs in the context of influenza and HIV has represented a major roadblock. Many possible explanations have been considered; however, none of the arguments proposed to date seem to fully recapitulate the observed counter-selection for broadly protective antibodies. Antibodies can influence antigen presentation by enhancing the processing of CD4 epitopes adjacent to the binding region while suppressing the overlapping ones. We analyze the relative positioning of dominant B and T cell epitopes in published antigens that elicit strong and poor humoral responses. In strong immunogenic antigens, regions bound by immunodominant antibodies are frequently adjacent to CD4 epitopes, potentially boosting their presentation. Conversely, poorly immunogenic regions targeted by bnAbs in HIV and influenza overlap with clusters of dominant CD4 epitopes, potentially conferring an intrinsic disadvantage for bnAb-bearing B cells in germinal centers. Here, we propose the theory of immunodominance relativity, according to which the relative positioning of immunodominant B and CD4 epitopes within a given antigen drives immunodominance. Thus, we suggest that the relative positioning of B-T epitopes may be one additional mechanism that cooperates with other previously described processes to influence immunodominance. If demonstrated, this theory can improve the current understanding of immunodominance, provide a novel explanation for HIV and influenza escape from humoral responses, and pave the way for a new rational design of universal vaccines.

Cross-reactivity of eight SARS-CoV-2 variants rationally predicts immunogenicity clustering in sarbecoviruses

A steep rise in Omicron reinfection cases suggests that this variant has increased immune evasion ability. To evaluate its antigenicity relationship with other variants, antisera from guinea pigs immunized with spike protein of SARS-CoV-2 variants of concern (VOCs) and variants of interest (VOIs) were cross-tested against pseudotyped variants. The neutralization activity against Omicron was markedly reduced when other VOCs or VOIs were used as immunogens, and Omicron (BA.1)-elicited sera did not efficiently neutralize the other variants. However, a Beta or Omicron booster, when administered as the 4th dose 3-months after the 3rd dose of any of the variants, could elicit broad neutralizing antibodies against all of the current variants including Omicron BA.1. Further analysis with 280 available antigen–antibody structures and quantification of immune escape from 715 reported neutralizing antibodies provide explanations for the observed differential immunogenicity. Three distinct clades predicted using an in silico algorithm for clustering of sarbecoviruses based on immune escape provide key information for rational design of vaccines.

Understanding the Phagocytosis of Particles: the Key for Rational Design of Vaccines and Therapeutics.

A robust comprehension of phagocytosis is crucial for understanding its importance in innate immunity. A detailed description of the molecular mechanisms that lead to the uptake and clearance of endogenous and exogenous particles has helped elucidate the role of phagocytosis in health and infectious or autoimmune diseases. Furthermore, knowledge about this cellular process is important for the rational design and development of particulate systems for the administration of vaccines or therapeutics. Depending on these specific applications and the required biological responses, particles must be designed to encourage or avoid their phagocytosis and prolong their circulation time. Functionalization with specific polymers or ligands and changes in the size, shape, or surface of particles have important effects on their recognition and internalization by professional and nonprofessional phagocytes and have a major influence on their fate and safety. Here, we review the phagocytosis of particles intended to be used as carrier or delivery systems for vaccines or therapeutics, the cells involved in this process depending on the route of administration, and the strategies employed to obtain the most desirable particles for each application through the manipulation of their physicochemical characteristics. We also offer a view of the challenges and potential opportunities in the field and give some recommendations that we expect will enable the development of improved approaches for the rational design of these systems.

Considerations of CD8+ T Cells for Optimized Vaccine Strategies Against Respiratory Viruses.

The primary goal of vaccines that protect against respiratory viruses appears to be the induction of neutralizing antibodies for a long period. Although this goal need not be changed, recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have drawn strong attention to another arm of acquired immunity, CD8+ T cells, which are also called killer T cells. Recent evidence accumulated during the coronavirus disease 2019 (COVID-19) pandemic has revealed that even variants of SARS-CoV-2 that escaped from neutralizing-antibodies that were induced by either infection or vaccination could not escape from CD8+ T cell-mediated immunity. In addition, although traditional vaccine platforms, such as inactivated virus and subunit vaccines, are less efficient in inducing CD8+ T cells, newly introduced platforms for SARS-CoV-2, namely, mRNA and adenoviral vector vaccines, can induce strong CD8+ T cell-mediated immunity in addition to inducing neutralizing antibodies. However, CD8+ T cells function locally and need to be at the site of infection to control it. To fully utilize the protective performance of CD8+ T cells, it would be insufficient to induce only memory cells circulating in blood, using injectable vaccines; mucosal immunization could be required to set up CD8+ T cells for the optimal protection. CD8+ T cells might also contribute to the pathology of the infection, change their function with age and respond differently to booster vaccines in comparison with antibodies. Herein, we overview cutting-edge ideas on CD8+ T cell-mediated immunity that can enable the rational design of vaccines for respiratory viruses.

Computational identification of HCV neutralizing antibodies with a common HCDR3 disulfide bond motif in the antibody repertoires of infected individuals.

Despite recent success in hepatitis C virus (HCV) treatment using antivirals, an HCV vaccine is still needed to prevent reinfections in treated patients, to avert the emergence of drug-resistant strains, and to provide protection for people with no access to the antiviral therapeutics. The early production of broadly neutralizing antibodies (bNAbs) associates with HCV clearance. Several potent bNAbs bind a conserved HCV glycoprotein E2 epitope using an unusual heavy chain complementarity determining region 3 (HCDR3) containing an intra-loop disulfide bond. Isolation of additional structurally-homologous bNAbs would facilitate the recognition of key determinants of such bNAbs and guide rational vaccine design. Here we report the identification of new antibodies containing an HCDR3 disulfide bond motif using computational screening with the Rosetta software. Using the newly-discovered and already-known members of this antibody family, we review the required HCDR3 amino acid composition and propose determinants for the bent versus straight HCDR3 loop conformation observed in these antibodies.

COVID-19 vaccine design using reverse and structural vaccinology, ontology-based literature mining and machine learning.

Rational vaccine design, especially vaccine antigen identification and optimization, is critical to successful and efficient vaccine development against various infectious diseases including coronavirus disease 2019 (COVID-19). In general, computational vaccine design includes three major stages: (i) identification and annotation of experimentally verified gold standard protective antigens through literature mining, (ii) rational vaccine design using reverse vaccinology (RV) and structural vaccinology (SV) and (iii) post-licensure vaccine success and adverse event surveillance and its usage for vaccine design. Protegen is a database of experimentally verified protective antigens, which can be used as gold standard data for rational vaccine design. RV predicts protective antigen targets primarily from genome sequence analysis. SV refines antigens through structural engineering. Recently, RV and SV approaches, with the support of various machine learning methods, have been applied to COVID-19 vaccine design. The analysis of post-licensure vaccine adverse event report data also provides valuable results in terms of vaccine safety and how vaccines should be used or paused. Ontology standardizes and incorporates heterogeneous data and knowledge in a human- and computer-interpretable manner, further supporting machine learning and vaccine design. Future directions on rational vaccine design are discussed.

Glycoprotein B Antibodies Completely Neutralize EBV Infection of B Cells.

The Epstein–Barr virus (EBV) is the first reported oncogenic herpesvirus that establishes persistent infection in B lymphocytes in 95% of adults worldwide. Glycoprotein B (gB) plays a predominant role in the fusion of the viral envelope with the host cell membrane. Hence, it is of great significance to isolate gB-specific fusion-inhibiting neutralizing antibodies (NAbs). AMMO5 is the only gB NAb but fails to antagonize B-cell infection. It is essential to isolate potent NAbs that can completely block EBV infection of B cells. Using hybridoma technology and neutralization assay, we isolate two gB NAbs 8A9 and 8C12 that are capable of completely neutralizing B-cell infection in vitro. In addition, 8A9 shows cross-reactivity with rhesus lymphocryptovirus (rhLCV) gB. Competitive binding experiments demonstrate that 8A9 and 8C12 recognize novel epitopes that are different from the AMMO5 epitope. The epitopes of 8A9 and 8C12 are mapped to gB D-II, and the AMMO5 epitope is located precisely at gB aa 410–419. We find that 8A9 and 8C12 significantly inhibit gB-derived membrane fusion using a virus-free fusion assay. In summary, this study identifies two gB-specific NAbs that potently block EBV infection of B cells. Our work highlights the importance of gB D-II as a predominant neutralizing epitope, and aids in the rational design of therapeutics or vaccines based on gB.

HIV Transmembrane Glycoprotein Conserved Domains and Genetic Markers Across HIV-1 and HIV-2 Variants.

HIV envelope transmembrane glycoproteins gp41 (HIV-1) and gp36 (HIV-2) present high variability and play a key role in the HIV-host cell membrane's fusion, as a target for human broadly neutralizing antibodies (bnAbs) and drugs. Thus, a better knowledge of amino acid (aa) conservation across structural domains and HIV variants can help to identify conserved targets to direct new therapeutic and diagnostic strategies. All available gp41/gp36 nucleotide sequences were downloaded from Los Alamos National Laboratory (LANL) HIV Sequence Database, selecting 17,078 sequences ascribed to HIV-1 and HIV-2 variants with ≥3 sequences. After aligning and translating into aa with MEGAv6.0, an in-house bioinformatics program (EpiMolBio) was used to identify the most conserved aa and the aa changes that were specific for each variant (V-markers) vs. HXB2/BEN (HIV-1/HIV-2) reference sequence. We analyzed the presence of specific aa changes among V-markers affecting infectivity, gp41 structure, function, or resistance to the enfuvirtide viral fusion inhibitor (T-20). We also inferred the consensus sequences per HIV variant, describing in each HIV-1 group (M, N, O, P) the conservation level along the complete gp41 per structural domain and locating in each binding site the anti-gp41 human Abs (bnAbs and non bnAbs) described in LANL. We found 38.3/59.7% highly conserved aa present in ≥90% of the 16,803/275 gp41/gp36 sequences ascribed to 105/3 HIV-1/HIV-2 variants, with 9/12.6% of them showing complete conservation across LANL sequences. The fusion peptide, its proximal region, the N-heptad repeat, and the membrane-proximal external region were the gp41 domains with ≥84% of conserved aa in the HIV-1 consensus sequence, the target of most Abs. No natural major resistance mutations to T-20 were observed. Our results show, for the first time, a complete conservation study of gp41/gp36 per variant in the largest panel of HIV variants analyzed to date, providing useful information for a more rational design of drugs, vaccines, and molecular detection tests targeting the HIV transmembrane glycoprotein.

An In Silico Analysis of Malaria Pre-Erythrocytic-Stage Antigens Interpreting Worldwide Genetic Data to Suggest Vaccine Candidate Variants and Epitopes.

Failure to account for genetic diversity of antigens during vaccine design may lead to vaccine escape. To evaluate the vaccine escape potential of antigens used in vaccines currently in development or clinical testing, we surveyed the genetic diversity, measured population differentiation, and performed in silico prediction and analysis of T-cell epitopes of ten such Plasmodium falciparum pre-erythrocytic-stage antigens using whole-genome sequence data from 1010 field isolates. Of these, 699 were collected in Africa (Burkina Faso, Cameroon, Guinea, Kenya, Malawi, Mali, and Tanzania), 69 in South America (Brazil, Colombia, French Guiana, and Peru), 59 in Oceania (Papua New Guinea), and 183 in Asia (Cambodia, Myanmar, and Thailand). Antigens surveyed include cell-traversal protein for ookinetes and sporozoites, circumsporozoite protein, liver-stage antigens 1 and 3, sporozoite surface proteins P36 and P52, sporozoite asparagine-rich protein-1, sporozoite microneme protein essential for cell traversal-2, and upregulated-in-infectious-sporozoite 3 and 4 proteins. The analyses showed that a limited number of these protein variants, when combined, would be representative of worldwide parasite populations. Moreover, predicted T-cell epitopes were identified that could be further explored for immunogenicity and protective efficacy. Findings can inform the rational design of a multivalent malaria vaccine.

Rational Vaccinology: Harnessing Nanoscale Chemical Design for Cancer Immunotherapy.

Cancer immunotherapy is a powerful treatment strategy that mobilizes the immune system to fight disease. Cancer vaccination is one form of cancer immunotherapy, where spatiotemporal control of the delivery of tumor-specific antigens, adjuvants, and/or cytokines has been key to successfully activating the immune system. Nanoscale materials that take advantage of chemistry to control the nanoscale structural arrangement, composition, and release of immunostimulatory components have shown significant promise in this regard. In this Outlook, we examine how the nanoscale structure, chemistry, and composition of immunostimulatory compounds can be modulated to maximize immune response and mitigate off-target effects, focusing on spherical nucleic acids as a model system. Furthermore, we emphasize how chemistry and materials science are driving the rational design and development of next-generation cancer vaccines. Finally, we identify gaps in the field that should be addressed moving forward and outline future directions to galvanize researchers from multiple disciplines to help realize the full potential of this form of cancer immunotherapy through chemistry and rational vaccinology.

Epitope-focused immunogen design based on the ebolavirus glycoprotein HR2-MPER region.

The three human pathogenic ebolaviruses: Zaire (EBOV), Bundibugyo (BDBV), and Sudan (SUDV) virus, cause severe disease with high fatality rates. Epitopes of ebolavirus glycoprotein (GP) recognized by antibodies with binding breadth for all three ebolaviruses are of major interest for rational vaccine design. In particular, the heptad repeat 2 –membrane-proximal external region (HR2-MPER) epitope is relatively conserved between EBOV, BDBV, and SUDV GP and targeted by human broadly-neutralizing antibodies. To study whether this epitope can serve as an immunogen for the elicitation of broadly-reactive antibody responses, protein design in Rosetta was employed to transplant the HR2-MPER epitope identified from a co-crystal structure with the known broadly-reactive monoclonal antibody (mAb) BDBV223 onto smaller scaffold proteins. From computational analysis, selected immunogen designs were produced as recombinant proteins and functionally validated, leading to the identification of a sterile alpha motif (SAM) domain displaying the BDBV-HR2-MPER epitope near its C terminus as a promising candidate. The immunogen was fused to one component of a self-assembling, two-component nanoparticle and tested for immunogenicity in rabbits. Robust titers of cross-reactive serum antibodies to BDBV and EBOV GPs and moderate titers to SUDV GP were induced following immunization. To confirm the structural composition of the immunogens, solution NMR studies were conducted and revealed structural flexibility in the C-terminal residues of the epitope. Overall, our study represents the first report on an epitope-focused immunogen design based on the structurally challenging BDBV-HR2-MPER epitope.

From Antibody Repertoires to Cell-Cell Interactions to Molecular Networks: Bridging Scales in the Germinal Center.

Antibody-mediated adaptive immunity must provide effective long-term protection with minimal adverse effects, against rapidly mutating pathogens, in a human population with diverse ages, genetics, and immune histories. In order to grasp and leverage the complexities of the antibody response, we advocate for a mechanistic understanding of the multiscale germinal center (GC) reaction – the process by which precursor B-cells evolve high-affinity antigen-specific antibodies, forming an effector repertoire of plasma and memory cells for decades-long protection. The regulatory dynamics of B-cells within the GC are complex, and unfold across multiple interacting spatial and temporal scales. At the organism scale, over weeks to years, the antibody sequence repertoire formed by various B-cell clonal lineages modulates antibody quantity and quality over time. At the tissue and cellular scale, over hours to weeks, B-cells undergo selection via spatially distributed interactions with local stroma, antigen, and helper T-cells. At the molecular scale, over seconds to days, intracellular signaling, transcriptional, and epigenetic networks modulate B-cell fates and shape their clonal lineages. We summarize our current understanding within each of these scales, and identify missing links in connecting them. We suggest that quantitative multi-scale mathematical models of B-cell and GC reaction dynamics provide predictive frameworks that can apply basic immunological knowledge to practical challenges such as rational vaccine design.

Three SARS-CoV-2 antibodies provide broad and synergistic neutralization against variants of concern, including Omicron.

The rapidly spreading Omicron variant is highly resistant to vaccines, convalescent sera, and neutralizing antibodies (nAbs), highlighting the urgent need for potent therapeutic nAbs. Here, a panel of human nAbs from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescent patients show diverse neutralization against Omicron, of which XMA01 and XMA04 maintain nanomolar affinities and excellent neutralization (half maximal inhibitory concentration [IC50]: ∼20 ng/mL). nAb XMA09 shows weak but unattenuated neutralization against all variants of concern (VOCs) as well as SARS-CoV. Structural analysis reveals that the above three antibodies could synergistically bind to the receptor-binding domains (RBDs) of both wild-type and Omicron spikes and defines the critical determinants for nAb-mediated broad neutralizations. Three nAbs confer synergistic neutralization against Omicron, resulting from the inter-antibody interaction between XMA04 and XMA01(or XMA09). Furthermore, the XMA01/XMA04 cocktail provides synergistic protection against Beta and Omicron variant infections in hamsters. In summary, our results provide insights for the rational design of antibody cocktail therapeutics or universal vaccines against Omicron.

Early post-vaccination gene signatures correlate with the magnitude and function of vaccine-induced HIV envelope-specific plasma antibodies in infant rhesus macaques

Abstract Systems vaccinology approaches are important tools in rational vaccine design. Our goal was to determine whether early innate immune responses to the vaccine prime in infant rhesus macaques, immunized with two different HIV envelope (Env) vaccine regimens, were associated with functional antibody responses in the memory phase. We compared plasma cytokine levels and molecular signatures of a 3M-052-SE adjuvanted HIV Env protein vaccine (n=10) to a regimen combining the adjuvanted HIV Env protein and MVA-HIV Env (n=10) at days (D) 0, 1, and 3 post the vaccine prime. Whole blood transcriptional profiling applying NanoString technology was employed to identify differentially expressed genes (DEG). Innate immune responses were correlated with vaccine-induced adaptive immune responses at weeks 14, 20, 32, and 34. The vaccine prime induced a rapid, but transient, increase in inflammatory plasma cytokines and changes in mRNA expression that peaked at D1. In the HIV protein group, we identified 31 DEG with increased mRNA levels, whereas a single, downregulated, DEG was identified in the MVA-Env plus Protein group. Day one signatures were positively correlated with week 14 Env-specific IgG responses, and, at week 34, with Env-specific follicular T helper cells and Env-specific antibody-dependent cytotoxicity function, but negatively correlated with Env-specific CD8+ T cell responses. A protein-protein interaction network confirmed that several of the DEG-encoded proteins have predicted interaction partners that are important for B cell activation. These results support the idea that vaccine-induced HIV-specific antibody and T cell responses can be optimized through the modulation of the vaccine prime. Supported by National Institutes of Health grants R01 DE028146 , P01 AI117915 , T32 5108303 , the Office of Research Infrastructure Programs/OD P510D011107 (CNPRC), and the Center for AIDS Research award P30AI050410

Requirement for robust T and B cell responses for immune protection against Powassan virus (POWV) in virus-like particle (VLP) vaccination.

Abstract Powassan virus (POWV) is a tick-borne pathogen for which humans are an incidental host. POWV infection can be fatal or result in long-term neurological sequelae; however, there are no approved vaccinations for POWV. Integral to efficacious vaccine development is the identification of correlates of immune protection, which we accomplished in this study by utilizing a murine model of POWV infection. Using POWV lethal and sub-lethal challenge models, we show that 1) robust B and T cell responses are necessary for immune protection, 2) POWV lethality can be attributed to both viral- and host-mediated drivers of disease and 3) knowledge of the immune correlates of protection against POWV can be applied in a virus-like particle (VLP)-based vaccination approach that provides protection from lethal POWV challenge. We also provide evidence that POWV-experienced CD8+ T cells may potentiate immune-mediated pathogenesis during infection. Identification of beneficial and detrimental aspects of POWV-immune protection is significant as it will aid in the rational design of POWV vaccines. This research was supported in part by the National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID): 5R01AI152192-02, 5R01AI137424-03 and F31AI152460-01. This research was also supported in part by the Department of Defense (Award#: PR192269). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.