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Safe and effective T cell vaccines are needed for the treatment or prevention of cancers as well as infectious agents where vaccines for neutralizing antibodies have performed poorly. Recent research highlights an important role for tissue-resident memory T cells (TRM cells) in protective immunity and the role of a subset of dendritic cells that are capable of cross-priming for the induction of TRM cells. However, efficient vaccine technologies that operate through cross-priming and induce robust CD8+ T cell responses are lacking. We developed a platform technology by genetically engineering the bovine papillomavirus L1 major capsid protein to insert a polyglutamic acid/cysteine motif in place of wild-type amino acids in the HI loop. Virus-like particles (VLPs) are formed by self-assembly in insect cells infected with a recombinant baculovirus. Polyarginine/cysteine-tagged antigens are linked to the VLP by a reversible disulfide bond. The VLP possesses self-adjuvanting properties due to the immunostimulatory activity of papillomavirus VLPs. Polyionic VLP vaccines induce robust CD8+ T cell responses in peripheral blood and tumor tissues. A prostate cancer polyionic VLP vaccine was more efficacious than other vaccines and immunotherapies for the treatment of prostate cancer in a physiologically relevant murine model and successfully treated more advanced diseases than the less efficacious technologies. The immunogenicity of polyionic VLP vaccines is dependent on particle size, reversible linkage of the antigen to the VLP, and an interferon type 1 and Toll-like receptor (TLR)3/7-dependent mechanism.

Cell-mediated immune responses are crucial for protecting the host against Toxoplasma gondii infection. However, impaired immunity, such as T-cell exhaustion, is a common phenomenon during chronic infection. This may represent a strategy employed by T. gondii to evade host defenses. T-cell immunoglobulin and mucin-domain containing 3 (Tim-3) is an important regulatory molecule involved in cell-mediated immunity. This study examined the expression of Tim-3 and the effects of its blockade in a mouse model of toxoplasmosis. In mice with chronic T. gondii infection, we found that Tim-3 is highly expressed in both cyst-bearing and non-cyst-bearing tissues, and its expression correlates with the parasite burden. Blocking the Tim-3 pathway with an anti-Tim-3 antibody enhances the immune response, resulting in elevated levels of cytokines (IFN-γ, IL-12p70, IL-2, IL-9) and the chemokine CXCL1 in the serum, increased leukocyte infiltration (CD3 + , CD14 + cells) in the brain, and downregulation of Tim-3 expression in microglial cells. As a result, the anti-Tim-3 treatment resulted in a 62% reduction in the number of tissue cysts and a trend towards an increase in the homeostatic signature, P2RY12, in microglia. Our study provides proof of concept for an anti-Tim-3 approach in treating chronic T. gondii infection and potentially other brain-residing pathogens.

Toxoplasma gondii can infect the host brain and trigger neuroinflammation. Such neuroinflammation might persist for years if the infection is not resolved, resulting in harmful outcomes for the brain. We have previously demonstrated the efficacy of immunotherapy targeting the programmed cell death protein 1 (PD-1) pathway on clearance of Toxoplasma tissue cysts. We aimed to test whether parasite clearance would lead to the resolution of neuroinflammation in infected brains. We established chronic Toxoplasma infection in BALB/c mice using the cyst-forming Prugniaud strain. Mice then received αPD-L1 or isotype control antibodies. After completion of the therapy, mice were euthanized six weeks later. The number of brain tissue cysts, Toxoplasma -specific CD8 + T cell proliferation and IFN-γ secretion, serum cytokine and chemokine levels, and CNS inflammation were measured. In αPD-L1-treated mice, we observed reduced brain tissue cysts, increased spleen weight, elevated IFN-γ production by antigen-specific CD8 + T cells, and a general increase in multiple serum cytokines and chemokines. Importantly, αPD-L1-treated mice displayed attenuation of meningeal lymphocytes, reactive astrocytes, and C1q expression. The reduction in inflammation-related proteins is correlated with reduced parasite burden. These results suggest that promoting systemic immunity results in parasite clearance, which in turn alleviates neuroinflammation. Our study may have implications for some brain infections where neuroinflammation is a critical component.

There is marked variation in the human response to Toxoplasma gondii infection. Epidemiological studies indicate associations between strain virulence and severity of toxoplasmosis. Animal studies on the pathogenic effect of chronic infection focused on relatively avirulent strains (e.g. type II) because they can easily establish latent infections in mice, defined by the presence of bradyzoite-containing cysts. To provide insight into virulent strain-related severity of human toxoplasmosis, we established a chronic model of the virulent type I strain using outbred mice. We found that type I-exposed mice displayed variable outcomes ranging from aborted to severe infections. According to antibody profiles, we found that most of mice generated antibodies against T. gondii organism but varied greatly in the production of antibodies against matrix antigen MAG1. There was a strong correlation between MAG1 antibody level and brain cyst burden in chronically infected mice (r = 0.82, p = 0.0021). We found that mice with high MAG1 antibody level displayed lower weight, behavioral changes, altered levels of gene expression and immune activation. The most striking change in behavior we discovered was a blunted response to amphetamine-trigged locomotor activity. The extent of most changes was directly correlated with levels of MAG1 antibody. These changes were not found in mice with less cyst burden or mice that were acutely but not chronically infected. Our finding highlights the critical role of cyst burden in a range of disease severity during chronic infection, the predictive value of MAG1 antibody level to brain cyst burden and to changes in behavior or other pathology in chronically infected mice. Our finding may have important implications for understanding the heterogeneous effects of T. gondii infections in human.

Oncogenic human papillomavirus (HPV) is a common genital infection that has the potential to develop into cervical cancer in some women. This Review summarises current knowledge on the mechanisms of host immunity that help prevent and control HPV infection and the viral factors that exist to avoid immune surveillance. Although most women clear the infection within a few months, the virus induces a shift towards immune tolerance that can facilitate persistence and permit tumorigenesis. Mechanisms used by HPV to avoid immune surveillance and control include infecting only the basal layer of the cervical epithelium, limiting expression of viral proteins until later stages of epithelial differentiation, undergoing non-lytic replication, and downregulating the expression of important receptors on cells of the innate immune system. Furthermore, HPV suppresses the expression of several proinflammatory proteins that are crucial in clearing infection and activating the cytotoxic T lymphocytes involved in killing virus-infected cells. Interestingly, neutralising antibodies, although of uncertain effectiveness in preventing infection or reinfection after natural exposure (prior infection), are highly protective after immunisation with HPV virus-like-particle-based vaccines. Understanding what is known and unknown about the interaction between the immune system and HPV is important in the assessment of the potential contribution of prophylactic vaccination in reducing the incidence of cervical cancer. However, despite our growing understanding, many aspects of the interactions between HPV and the host immune system remain unknown, and this Review draws attention to several of these unresolved issues and their implications.

BK polyomavirus (BKV or BKPyV) associated nephropathy affects up to 10% of kidney transplant recipients (KTRs). BKV isolates are categorized into four genotypes. It is currently unclear whether the four genotypes are also serotypes. To address this issue, we developed high-throughput serological assays based on antibody-mediated neutralization of BKV genotype I and IV reporter vectors (pseudoviruses). Neutralization-based testing of sera from mice immunized with BKV-I or BKV-IV virus-like particles (VLPs) or sera from naturally infected human subjects revealed that BKV-I specific serum antibodies are poorly neutralizing against BKV-IV and vice versa. The fact that BKV-I and BKV-IV are distinct serotypes was less evident in traditional VLP-based ELISAs. BKV-I and BKV-IV neutralization assays were used to examine BKV type-specific neutralizing antibody responses in KTRs at various time points after transplantation. At study entry, sera from 5% and 49% of KTRs showed no detectable neutralizing activity for BKV-I or BKV-IV neutralization, respectively. By one year after transplantation, all KTRs were neutralization seropositive for BKV-I, and 43% of the initially BKV-IV seronegative subjects showed evidence of acute seroconversion for BKV-IV neutralization. The results suggest a model in which BKV-IV-specific seroconversion reflects a de novo BKV-IV infection in KTRs who initially lack protective antibody responses capable of neutralizing genotype IV BKVs. If this model is correct, it suggests that pre-vaccinating prospective KTRs with a multivalent VLP-based vaccine against all BKV serotypes, or administration of BKV-neutralizing antibodies, might offer protection against graft loss or dysfunction due to BKV associated nephropathy.

Men who have sex with men (MSM) are more vulnerable to blood-borne infections and/or sexually-transmitted infections (STI). This study was conducted to estimate the prevalences of mono and co-infections of HIV-1 and other blood-borne/STIs in a sample of MSM in Campinas, Brazil. Responding Driven Sampling (RDS) was used for recruitment of MSM. Serum samples collected from 558 MSM were analyzed for the presence of serological markers for HIV-1, HBV, HCV, HTLV, HPV-16/18, and T. pallidum infections. The highest prevalences of infection in serum samples were found for HPV-16 and 18 (31.9% and 20.3%, respectively). Approximately 8% of the study population showed infection with HIV-1, and within that group, 27.5% had recently become infected with HIV-1. HBV infection and syphilis were detected in 11.4% and 10% of the study population, respectively, and the rates of HTLV and HCV infection were 1.5% and 1%, respectively. With the exception of HTLV, all other studied infections were usually found as co-infections rather then mono-infections. The rates of co-infection for HCV, HPV-18, and HIV-1 were the highest among the studied infections (100%, 83%, and 85%, respectively). Interestingly, HTLV infection was usually found as a mono-infection in the study group, whereas HCV was found only as a co-infection. The present findings highlight the need to educate the MSM population concerning their risk for STIs infections and methods of prevention. Campaigns to encourage vaccination against HBV and HPV could decrease the rates of these infections in MSM.

Virus-like particles (VLPs) are promising vaccine technology due to their safety and ability to elicit strong immune responses. Chimeric VLPs can extend this technology to low immunogenicity foreign antigens. However, insertion of foreign epitopes into the sequence of self-assembling proteins can have unpredictable effects on the assembly process. We aimed to generate chimeric bovine papillomavirus (BPV) VLPs displaying a repetitive array of polyanionic docking sites on their surface. These VLPs can serve as platform for covalent coupling of polycationic fusion proteins. We generated baculoviruses expressing chimeric BPV L1 protein with insertion of a polyglutamic-cysteine residue in the BC, DE, HI loops and the H4 helix. Expression in insect cells yielded assembled VLPs only from insertion in HI loop. Insertion in DE loop and H4 helix resulted in partially formed VLPs and capsomeres, respectively. The polyanionic sites on the surface of VLPs and capsomeres were decorated with a polycationic MUC1 peptide containing a polyarginine-cysteine residue fused to 20 amino acids of the MUC1 tandem repeat through electrostatic interactions and redox-induced disulfide bond formation. MUC1-conjugated fully assembled VLPs induced robust activation of bone marrow-derived dendritic cells, which could then present MUC1 antigen to MUC1-specific T cell hybridomas and primary naïve MUC1-specific T cells obtained from a MUC1-specific TCR transgenic mice. Immunization of human MUC1 transgenic mice, where MUC1 is a self-antigen, with the VLP vaccine induced MUC1-specific CTL, delayed the growth of MUC1 transplanted tumors and elicited complete tumor rejection in some animals.

The recent outbreak of monkeypox virus (MPXV) has caused global concern. How the virus evades the interferon (IFN) response is still poorly understood. We analyzed type I/II IFN (IFN-I/II) expression in clinical samples from MPXV-infected patients and measured IFN-I kinetics in MPXV-infected cells. We also evaluated the anti-MPXV activity of IFN-I/II in A549, HeLa and Vero-E6 cell lines. IFN-I/II mRNA expression was detected in skin lesions, anal swabs, nasopharyngeal samples and peripheral blood mononuclear cells (PBMC), with the highest levels in skin lesions (p < 0.05). High MPXV DNA levels in clinical samples were associated with increased IFN-I levels. In vitro, MPXV infection induced a peak of IFN-I between 48 and 72 h post-infection (p < 0.01). Pre-treatment of the A549, HeLa and Vero-E6 cells with high concentrations (≥ 100,000 International Unit, IU/ml) of IFN-α and IFN-ω did not inhibit or had little effect on MPXV replication, while IFN-β moderately reduced MPXV replication by 2.7–1.5 log10 at 100,000 IU/ml. In clinical samples there was a trend for elevated levels of IFN-γ in association with lower MPXV load and in vitro IFN-γ (3,600 IU/ml) strongly reduced viral titers by 3.4–1.6 log10. There were no significant differences in expression of select IFN-stimulated genes (ISGs) in MPXV infection in vitro. This study shows that MPXV delays IFN-I induction and inhibits expression of selected ISGs in vitro and is associated with an IFN-I resistance phenotype in vivo. However, MPXV is less resistant to IFN-γ in vivo and is sensitive to IFN-γ treatment in vitro, suggesting a potential therapeutic role for IFN-γ.

Prostate cancer is a candidate for immunotherapy because cancer cells express tissue-specific proteins that can be therapeutic targets. However, immune checkpoint inhibitors and active immunization have performed poorly in clinical trials. We developed a novel virus-like particle (VLP) vaccine composed of bovine papillomavirus L1 protein engineered to display surface docking sites. We decorated VLPs with peptides encoding T cell epitopes from two prostate cancer-associated tumor antigens, prostate stem cell antigen (PSCA), and prostatic acid phosphatase (PAP-1 and PAP-2), and a neo-antigen, stimulator of prostatic adenocarcinoma-specific T cells (SPAS-1). The VLP vaccines induced a mean frequency of antigen-specific IFN-γ secreting CD8 + T cells of 2.9% to PSCA, 9.5% to SPAS-1, 0.03% to PAP-1, and 0.03% to PAP-2 in tumor-bearing TRAMP mice. We treated TRAMP mice at 19–20 weeks of age, when mice have advanced stages of carcinogenesis, with either VLP vaccine, anti-PD1 antibody, or combination immunotherapy. The VLP vaccine alone or in combination with anti-PD1 antibody significantly reduced tumor burden, while anti-PD1 antibody had a modest non-significant therapeutic effect. All treatments significantly increased CD3 + and CD8 + T cell infiltration into tumor tissue compared to control mice, and combination therapy resulted in significantly greater CD3 + and CD8 + T cell infiltration than monotherapy. Reduction in tumor burden in vaccine-treated mice was inversely correlated with CD8 + T cell numbers in tumor tissue. No other immunotherapy has shown efficacy in this animal model of advanced prostate cancer, making bovine papillomavirus VLPs an attractive vaccine technology to test in patients with metastatic prostate cancer.