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The clinical development of an effective Chlamydia vaccine requires in-depth understanding of how well protective pre-clinical immune signatures translate to humans. Here, we report a comparative immunological characterization of CTH522/CAF®01 in female mice and humans. We find a range of immune signatures that translate from mouse to human, including a Th1/Th17 cytokine profile and antibody functionality. We identify vaccine-induced T cell epitopes, conserved among Chlamydia serovars, and previously found in infected individuals. Using the mouse model, we show that the common immune signature protected against ascending infection in mice, and vaccine induced antibodies could delay bacterial ascension to the oviduct, as well as development of pathology, in a T cell depleted mouse model. Finally, we demonstrate long-lasting immunity and protection of mice one year after vaccination. Based on the results obtained in the present study, we propose to further investigate CTH522/CAF®01 in a phase IIb study. Authors present a comparative immunological characterisation of Chlamydia vaccine, CTH522/CAF®01, in mice and humans. Findings suggest the mouse to be a good predictor of human immunity to the Chlamydia vaccine CTH522/CAF®01, and long-lasting protection in the mouse further supports the development of this promising vaccine candidate.

The requirement for vaccine-induced tissue-resident immunity for protection against one or repeated infections with Chlamydia trachomatis (C.t.) is still not fully resolved. In this study, our aim was to investigate to which degree tissue-resident Th1/Th17 T cells in the genital tract (GT) could add to the protection mediated by circulating immunity. Out of several mucosal vaccine strategies, a strategy termed SIM (for simultaneous intrauterine and parenteral immunization with CAF01 adjuvanted CTH522), was superior in generating genital tract tissue-resident Th1/Th17 T cell immunity. This led to a faster and stronger local CD4 T cell response post infection, consisting of multifunctional IFNγ/TNFα-producing Th1 T cells and IFNγ/TNFα/IL-17-producing Th17 T cells, and a faster recruitment of innate immune cells. Post infection, SIM animals showed an additional significant reduction in bacterial levels compared to mice having received only a parenteral vaccine. Nevertheless, the parenteral strategy reduced bacterial levels by 75%, and interestingly, post infection, these mice generated their own vaccine-derived genital tract tissue-resident memory Th1/Th17 T cells, which upon a subsequent infection showed as fast an activation in the genital tract, as observed in SIM mice. Furthermore, in contrast to after the first infection, both groups of mice now showed a similar infection-induced boost in local vaginal IgA and IgG titers. Thus, vaccine-induced resident immunity, generated pre-infection, led to an advantage in the response against the first infection, but not the second infection, suggesting that a parenteral vaccine strategy is a suitable vaccine strategy against infections with Chlamydia trachomatis .

It is estimated that one-third of the world's population is infected with Mycobacterium tuberculosis. Infection typically remains latent, but it can reactivate to cause clinical disease. The only vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG), is largely ineffective, and ways to enhance its efficacy are being developed. Of note, the candidate booster vaccines currently under clinical development have been designed to improve BCG efficacy but not prevent reactivation of latent infection. Here, we demonstrate that administering a multistage vaccine that we term H56 in the adjuvant IC31 as a boost to vaccination with BCG delays and reduces clinical disease in cynomolgus macaques challenged with M. tuberculosis and prevents reactivation of latent infection. H56 contains Ag85B and ESAT-6, which are two of the M. tuberculosis antigens secreted in the acute phase of infection, and the nutrient stress-induced antigen Rv2660c. Boosting with H56/IC31 resulted in efficient containment of M. tuberculosis infection and reduced rates of clinical disease, as measured by clinical parameters, inflammatory markers, and improved survival of the animals compared with BCG alone. Boosted animals showed reduced pulmonary pathology and extrapulmonary dissemination, and protection correlated with a strong recall response against ESAT-6 and Rv2660c. Importantly, BCG/H56-vaccinated monkeys did not reactivate latent infection after treatment with anti-TNF antibody. Our results indicate that H56/IC31 boosting is able to control late-stage infection with M. tuberculosis and contain latent tuberculosis, providing a rationale for the clinical development of H56.

The ESX systems from Mycobacterium tuberculosis are responsible for the secretion of highly immunogenic proteins of key importance for bacterial survival and growth. The two prototypic proteins, ESAT-6 (EsxA from ESX-1) and TB10.4 (EsxH from ESX-3) share a lot of characteristics regarding genome organization, size, antigenic properties, and vaccine potential but the two molecules clearly have very different roles in bacterial physiology. To further investigate the role of ESAT-6 and TB10.4 as preventive and post-exposure tuberculosis vaccines, we evaluated four different fusion-protein vaccines; H1, H4, H56 and H28, that differ only in these two components. We found that all of these vaccines give rise to protection in a conventional prophylactic vaccination model. In contrast, only the ESAT-6-containing vaccines resulted in significant protection against reactivation, when administered post-exposure. This difference in post-exposure activity did not correlate with a difference in gene expression during infection or a differential magnitude or quality of the vaccine-specific CD4 T cells induced by ESAT-6 versus TB10.4-containing vaccines. The post-exposure effect of the ESAT-6 based vaccines was found to be influenced by the infectious load at the time-point of vaccination and was abolished in chronically infected animals with high bacterial loads at the onset of vaccination. Our data demonstrate that there are specific requirements for the immune system to target an already established tuberculosis infection and that ESAT-6 has a unique potential in post-exposure vaccination strategies.

The current vaccine against tuberculosis (TB), BCG, has failed to control TB worldwide and the protective efficacy is moreover limited to 10-15 years. A vaccine that could efficiently boost a BCG-induced immune response and thus prolong protective immunity would therefore have a significant impact on the global TB-burden. In the present study we show that the fusion protein HyVac4 (H4), consisting of the mycobacterial antigens Ag85B and TB10.4, given in the adjuvant IC31® or DDA/MPL effectively boosted and prolonged immunity induced by BCG, leading to improved protection against infection with virulent M. tuberculosis (M.tb). Increased protection correlated with an increased percentage of TB10.4 specific IFNγ/TNFα/IL-2 or TNFα/IL-2 producing CD4 T cells at the site of infection. Moreover, this vaccine strategy did not compromise the use of ESAT-6 as an accurate correlate of disease development/vaccine efficacy. Indeed both CD4 and CD8 ESAT-6 specific T cells showed significant correlation with bacterial levels. H4-IC31® can efficiently boost BCG-primed immunity leading to an increased protective anti-M.tb immune response dominated by IFNγ/TNFα/IL-2 or TNFα/IL2 producing CD4 T cells. H4 in the CD4 T cell inducing adjuvant IC31® is presently in clinical trials.

A vaccine to control S. pyogenes infection is desperately warranted. S. pyogenes colonizes the upper respiratory tract (URT) and skin, from where it can progress to invasive and immune-mediated diseases. Infections with Streptococcus pyogenes and their sequelae are responsible for an estimated 18 million cases of serious disease with >700 million new primary cases and 500,000 deaths per year. Despite the burden of disease, there is currently no vaccine available for this organism. Here, we define a combination vaccine P*17/K4S2 comprising of 20-mer B-cell peptide epitopes, p*17 (a mutant derived from the highly conserved C3-repeat region of the M-protein), and K4S2 (derived from the streptococcal anti-neutrophil factor, Spy-CEP). The peptides are chemically conjugated to either diphtheria toxoid (DT) or a nontoxic mutant form of diphtheria toxin, CRM197. We demonstrate that a prime-pull immunization regimen involving two intramuscular inoculations with P*17/K4S2 adjuvanted with a two-component liposomal adjuvant system (CAF01; developed by Statens Serum Institut [SSI], Denmark), followed by an intranasal inoculation of unadjuvanted vaccine (in Tris) induces peptide- and S. pyogenes -binding antibodies and protects from mucosal and skin infection with hypervirulent covR/S mutant organisms. Prior vaccination with DT does not diminish the response to the conjugate peptide vaccines. Detailed Good Laboratory Practice (GLP) toxicological evaluation in male and female rats did not reveal any gross or histopathological adverse effects. IMPORTANCE A vaccine to control S. pyogenes infection is desperately warranted. S. pyogenes colonizes the upper respiratory tract (URT) and skin, from where it can progress to invasive and immune-mediated diseases. Global mortality estimates for S. pyogenes -associated diseases exceeds 500,000 deaths per year. S. pyogenes utilizes antigenic variation as a defense mechanism to circumvent host immune responses and thus a successful vaccine needs to provide strain-transcending and multicompartment (mucosal and skin) immunity. By defining highly conserved and protective epitopes from two critical virulence factors (M-protein and Spy-CEP) and combining them with a potent immunostimulant, CAF®01, we are addressing an unmet clinical need for a mucosally and skin-active subunit vaccine. We demonstrate that prime-pull immunization (2× intramuscular injections followed by intranasal immunization) promotes high sustained antibody levels in the airway mucosa and serum and protects against URT and invasive disease.

Streptococcus pyogenes (group A streptococcus, GAS) is responsible for a wide array of infections. Respiratory transmission via droplets is the most common mode of transmission but it may also infect the host via other routes such as lesions in the skin. To advance the development of a future vaccine against GAS, it is therefore important to investigate how protective immunity is related to the route of vaccine administration. To explore this, we examined whether a parenterally administered anti-GAS vaccine could protect against an intranasal GAS infection or if this would require locally primed immunity. We foundd that a parenteral CAF01 adjuvanted GAS vaccine offered no protection against intranasal infection despite inducing strong systemic Th1/Th17/IgG immunity that efficiently protected against an intraperitoneal GAS infection. However, the same vaccine administered via the intranasal route was able to induce protection against repeated intranasal GAS infections in a murine challenge model. The lack of intranasal protection induced by the parenteral vaccine correlated with a reduced mucosal recall response at the site of infection. Taken together, our results demonstrate that locally primed immunity is important for the defense against intranasal infection with Streptococcus pyogenes.

The development of new low cost inactivated polio virus based vaccines (IPV) is a high priority, and will be required to eradicate polio. In addition, such a vaccine constitutes the only realistic polio vaccine in the post-eradication era. One way to reduce the cost of a vaccine is to increase immunogenicity by use of adjuvants. The CAF01 adjuvant has previously been shown to be a safe and potent adjuvant with several antigens, and here we show that in mice IPV formulated with CAF01 induced increased systemic protective immunity measured by binding and neutralization antibody titers in serum. CAF01 also influenced the kinetics of both the cellular and humoral response against IPV to produce a faster, as well as a stronger, response, dominated by IgG2a, IgG2b, and IgG2c isotypes as well as IPV specific T cells secreting IFN-γ/IL-2. Finally, as intestinal immunity is also a priority of polio vaccines, we present a vaccine strategy based on simultaneous priming at an intradermal and an intramuscular site that generate intestinal immune responses against polio virus. Taken together, the IPV-CAF01 formulation constitutes a new promising vaccine against polio with the ability to generate strong humoral and cellular immunity against the polio virus.

Trachoma is a leading cause of infection-related blindness worldwide. This disease is caused by recurrent Chlamydia trachomatis (Ct) infections of the conjunctiva and develops in two phases: i) active (acute trachoma, characterized by follicular conjunctivitis), then long-term: ii) scarring (chronic trachoma, characterized by conjunctival fibrosis, corneal opacification and eyelid malposition). Scarring trachoma is driven by the number and severity of reinfections. The immune system plays a pivotal role in trachoma including exacerbation of the disease. Hence the immune system may also be key to developing a trachoma vaccine. Therefore, we characterized clinical and local immune response kinetics in a non-human primate model of acute conjunctival Ct infection and disease. The conjunctiva of non-human primate (NHP, Cynomolgus monkeys-Macaca fascicularis-) were inoculated with Ct (B/Tunis-864 strain, B serovar). Clinical ocular monitoring was performed using a standardized photographic grading system, and local immune responses were assessed using multi-parameter flow cytometry of conjunctival cells, tear fluid cytokines, immunoglobulins, and Ct quantification. Clinical findings were similar to those observed during acute trachoma in humans, with the development of typical follicular conjunctivitis from the 4th week post-exposure to the 11th week. Immunologic analysis indicated an early phase influx of T cells in the conjunctiva and elevated interleukins 4, 8, and 5, followed by a late phase monocytic influx accompanied with a decrease in other immune cells, and tear fluid cytokines returning to initial levels. Our NHP model accurately reproduces the clinical signs of acute trachoma, allowing for an accurate assessment of the local immune responses in infected eyes. A progressive immune response occurred for weeks after exposure to Ct, which subsided into a persistent innate immune response. An understanding of these local responses is the first step towards using the model to assess new vaccine and therapeutic strategies for disease prevention.

Mucosal immunity is important for the protection against a wide variety of pathogens. Traditional vaccines administered via parenteral routes induce strong systemic immunity, but they often fail to generate mucosal IgA. In contrast, bacteria-based vaccines comprise an appealing strategy for antigen delivery to mucosal sites. Vaginal infection with Chlamydia trachomatis can develop into upper genital tract infections that can lead to infertility. Therefore, the development of an effective vaccine against Chlamydia is a high priority. In the present study, we have explored the use of a common lactic acid bacterium, Lactobacillus plantarum, as a vector for delivery of a C. trachomatis antigen to mucosal sites. The antigen, referred as Hirep2 (H2), was anchored to the surface of L. plantarum cells using an N-terminal lipoprotein anchor. After characterization, the constructed strain was used as an immunogenic agent in mice. We explored a heterologous prime-boost strategy, consisting of subcutaneous priming with soluble H2 antigen co-administered with CAF01 adjuvant, followed by an intranasal boost with H2-displaying L. plantarum. The results show that, when used as a booster, the recombinant L. plantarum strain was able to evoke cellular responses. Most importantly, booster immunization with the Lactobacillus-based vaccine induced generation of antigen-specific IgA in the vaginal cavity.