Cross-species Protection Research Articles

Serological responses to target Streptococcus pyogenes vaccine antigens in patients with proven invasive beta-haemolytic streptococcal infections.

Rising incidence of invasive beta-haemolytic streptococcal (iBHS) infections has prompted consideration of vaccination as a preventative strategy for at-risk populations. The benefits of a vaccine targeting Lancefield group A (Streptococcus pyogenes; Strep A) would increase if cross-species immunity against Lancefield groups C/G (Streptococcus dysgalactiae subspecies equisimilis; SDSE) and B (Streptococcus agalactiae; GBS) was demonstrated. A prospective, observational study of adult patients with iBHS infections due to Strep A, SDSE or GBS. Antibody responses to six Strep A candidate antigens were assayed on acute and convalescent sera. A serological response was defined as an increase of >0.2log10 arbitrary units/mL (AU/mL). Sixty-seven participants were enrolled. Thirty-three participants were included in the final analysis (12, 11 and 10 with Strep A, SDSE and GBS, respectively). The median serological response for participants with Strep A was significant for all tested antigens (median >0.2log10 difference between acute and convalescent samples; P<0.05 for all). Those with SDSE had comparable and significant median (IQR) responses to streptolysin-O (0.65 [0.36-1.67], P=0.004), S. pyogenes adhesion and division protein (0.68 [0.36-1.63], P=0.005) and C5a peptidase (ScpA; 0.30 [0.23-1.06]), P=0.004). GBS responses were limited to ScpA only (0.34 [0.08-0.52], P=0.05). Patients with invasive Strep A infection mount robust antibody responses to six non-M protein vaccine candidate antigens. Similar significant responses to C5a peptidase in those with invasive SDSE and GBS infection highlight the importance of further research into cross-species protection and immunological correlates of vaccine efficacy.

CHALLENGES IN DEVELOPING VACCINE FOR CANINE DISTEMPER

The Canine Distemper Virus (CDV) represents a considerable risk to domestic and wild carnivore populations globally, notwithstanding the existence of vaccinations. This study examines the significant obstacles in creating successful CDV vaccines, especially regarding virus evolution, immune evasion, cross-species transmission, and vaccine reluctance. This review aims to consolidate existing research on CDV vaccine development, emphasizing emerging technologies, such as nanoparticle and DNA vaccines, and their capacity to address present challenges in immunogenicity and cross-species protection. Through the analysis of recent findings, this review delineates significant gaps in the comprehension of CDV's genetic variety of CDVs, the sustainability of wildlife reservoirs, and the obstacles to attaining extensive vaccination coverage. This review evaluates the influence of public health infrastructure and socioeconomic factors on vaccination distribution and uptake constraints, particularly in developing areas. These findings highlight the significance of a One Health approach, which amalgamates veterinary, wildlife, and public health viewpoints to address CDV epidemics more efficiently. Future research should focus on augmenting vaccine efficacy in non-domestic species, increasing public awareness of immunization initiatives, and creating thermostable vaccines for improved distribution accessibility. This review offers critical insights into the intricacies of the CDV vaccination and presents a framework for enhancing worldwide initiatives to combat this destructive virus.

Adjuvant-dependent impacts on vaccine-induced humoral responses and protection in preclinical models of nasal and genital colonization by pathogenic Neisseria.

Neisseria gonorrhoeae, which causes the sexually transmitted infection gonorrhea and N. meningitidis, a leading cause of bacterial meningitis and septicemia, are closely related human-restricted pathogens that inhabit distinct primary mucosal niches. While successful vaccines against invasive meningococcal disease have been available for decades, the rapid rise in antibiotic resistance has led to an urgent need to develop an effective gonococcal vaccine. Several surface antigens are shared among these two pathogens, making cross-species protection an exciting prospect. However, the type of vaccine-mediated immune response required to achieve protection against respiratory versus genital infection remains ill defined. In this study, we utilize well established mouse models of female lower genital tract colonization by N. gonorrhoeae and upper respiratory tract colonization by N. meningitidis to examine the performance of transferrin binding protein B (TbpB) vaccines formulated with immunologically distinct vaccine adjuvants. We demonstrate that vaccine-mediated protection is influenced by the choice of adjuvant, with Th1/2-balanced adjuvants performing optimally against N. gonorrhoeae, and both Th1/2-balanced and Th2-skewing adjuvants leading to a significant reduction in N. meningitidis burden. We further establish a lack of correlation between protection status and the humoral response or bactericidal titre. Combined, this work provides supports the feasibility for a single vaccine formulation to achieve pan-neisserial coverage.

Multistage protective anti-CelTOS monoclonal antibodies with cross-species sterile protection against malaria

CelTOS is a malaria vaccine antigen that is conserved in Plasmodium and other apicomplexan parasites and plays a role in cell-traversal. The structural basis and mechanisms of CelTOS-induced protective immunity to parasites are unknown. Here, CelTOS-specific monoclonal antibodies (mAbs) 7g7 and 4h12 demonstrated multistage activity, protecting against liver infection and preventing parasite transmission to mosquitoes. Both mAbs demonstrated cross-species activity with sterile protection against in vivo challenge with transgenic parasites containing either P. falciparum or P. vivax CelTOS, and with transmission reducing activity against P. falciparum. The mAbs prevented CelTOS-mediated pore formation providing insight into the protective mechanisms. X-ray crystallography and mutant-library epitope mapping revealed two distinct broadly conserved neutralizing epitopes. 7g7 bound to a parallel dimer of CelTOS, while 4h12 bound to a novel antiparallel dimer architecture. These findings inform the design of antibody therapies and vaccines and raise the prospect of a single intervention to simultaneously combat P. falciparum and P. vivax malaria.

High frequencies of alpha common cold coronavirus/SARS-CoV-2 cross-reactive functional CD4+ and CD8+ memory T cells are associated with protection from symptomatic and fatal SARS-CoV-2 infections in unvaccinated COVID-19 patients.

Cross-reactive SARS-CoV-2-specific memory CD4+ and CD8+ T cells are present in up to 50% of unexposed, pre-pandemic, healthy individuals (UPPHIs). However, the characteristics of cross-reactive memory CD4+ and CD8+ T cells associated with subsequent protection of asymptomatic coronavirus disease 2019 (COVID-19) patients (i.e., unvaccinated individuals who never develop any COVID-19 symptoms despite being infected with SARS-CoV-2) remains to be fully elucidated. This study compares the antigen specificity, frequency, phenotype, and function of cross-reactive memory CD4+ and CD8+ T cells between common cold coronaviruses (CCCs) and SARS-CoV-2. T-cell responses against genome-wide conserved epitopes were studied early in the disease course in a cohort of 147 unvaccinated COVID-19 patients who were divided into six groups based on the severity of their symptoms. Compared to severely ill COVID-19 patients and patients with fatal COVID-19 outcomes, the asymptomatic COVID-19 patients displayed significantly: (i) higher rates of co-infection with the 229E alpha species of CCCs (α-CCC-229E); (ii) higher frequencies of cross-reactive functional CD134+CD137+CD4+ and CD134+CD137+CD8+ T cells that cross-recognized conserved epitopes from α-CCCs and SARS-CoV-2 structural, non-structural, and accessory proteins; and (iii) lower frequencies of CCCs/SARS-CoV-2 cross-reactive exhausted PD-1+TIM3+TIGIT+CTLA4+CD4+ and PD-1+TIM3+TIGIT+CTLA4+CD8+ T cells, detected both ex vivo and in vitro. These findings (i) support a crucial role of functional, poly-antigenic α-CCCs/SARS-CoV-2 cross-reactive memory CD4+ and CD8+ T cells, induced following previous CCCs seasonal exposures, in protection against subsequent severe COVID-19 disease and (ii) provide critical insights into developing broadly protective, multi-antigen, CD4+, and CD8+ T-cell-based, universal pan-Coronavirus vaccines capable of conferring cross-species protection.

A bacterial pigment provides cross-species protection from H2O2- and neutrophil-mediated killing.

Bacterial infections are often polymicrobial. Pseudomonas aeruginosa and Staphylococcus aureus cause chronic co-infections, which are more problematic than mono-species infections. Understanding the mechanisms of their interactions is crucial for treating co-infections. Staphyloxanthin (STX), a yellow pigment synthesized by the S. aureus crt operon, promotes S. aureus resistance to oxidative stress and neutrophil-mediated killing. We found that STX production by S. aureus, either as surface-grown macrocolonies or planktonic cultures, was elevated when exposed to the P. aeruginosa exoproduct, 2-heptyl-4-hydroxyquinoline N-oxide (HQNO). This was observed with both mucoid and non-mucoid P. aeruginosa strains. The induction phenotype was found in a majority of P. aeruginosa and S. aureus clinical isolates examined. When subjected to hydrogen peroxide or human neutrophils, P. aeruginosa survival was significantly higher when mixed with wild-type (WT) S. aureus, compared to P. aeruginosa alone or with an S. aureus crt mutant deficient in STX production. In a murine wound model, co-infection with WT S. aureus, but not the STX-deficient mutant, enhanced P. aeruginosa burden and disease compared to mono-infection. In conclusion, we identified a role for P. aeruginosa HQNO mediating polymicrobial interactions with S. aureus by inducing STX production, which consequently promotes resistance to the innate immune effectors H2O2 and neutrophils. These results further our understanding of how different bacterial species cooperatively cause co-infections.

Generation of recombinant mAbs to vaccinia virus displaying high affinity and potent neutralization.

Members of the Orthopoxvirus genus can cause severe infections in humans. Global vaccination against smallpox, caused by the variola virus, resulted in the eradication of the disease in 1980. Shortly thereafter, vaccination was discontinued, and as a result, a large proportion of the current population is not protected against orthopoxviruses. The concerns that the variola virus or other engineered forms of poxviruses may re-emerge as bioweapons and the sporadic outbreaks of zoonotic members of the family, such as Mpox, which are becoming more frequent and prevalent, also emphasize the need for an effective treatment against orthopoxviruses. To date, the most effective way to prevent or control an orthopoxvirus outbreak is through vaccination. However, the traditional vaccinia-based vaccine may cause severe side effects. Vaccinia immune globulin was approved by the U.S. Food and Drug Administration (FDA) for the treatment of vaccine adverse reactions and was also used occasionally for the treatment of severe orthopoxvirus infections. However, this treatment carries many disadvantages and is also in short supply. Thus, a recombinant alternative is highly needed. In this study, two non-human primates were immunized with live vaccinia virus, producing a robust and diverse antibody response. A phage-display library was constructed based on the animal's lymphatic organs, and a panel of neutralizing monoclonal antibodies (mAbs), recognizing diverse proteins of the vaccinia virus, was selected and characterized. These antibodies recognized both mature virion and enveloped virion forms of the virus and exhibited high affinity and potent in vitro neutralization capabilities. Furthermore, these monoclonal antibodies were able to neutralize Mpox 2018 and 2022 strains, suggesting a potential for cross-species protection. We suggest that a combination of these mAbs has the potential to serve as recombinant therapy both for vaccinia vaccine adverse reactions and for orthopoxvirus infections. IMPORTANCE In this manuscript, we report the isolation and characterization of several recombinant neutralizing monoclonal antibodies (mAbs) identified by screening a phage-display library constructed from lymphatic cells collected from immunized non-human primates. The antibodies target several different antigens of the vaccinia virus, covering both mature virion and extracellular enveloped virion forms of the virus. We document strong evidence indicating that they exhibit excellent affinity to their respective antigens and, most importantly, optimal in vitro neutralization of the virus, which exceeded that of vaccinia immune globulin. Furthermore, we present the ability of these novel isolated mAbs (as well as the sera collected from vaccinia-immunized animals) to neutralize two Mpox strains from the 2018 to 2022 outbreaks. We believe that these antibodies have the potential to be used for the treatment of vaccinia vaccine adverse reactions, for other orthopoxvirus infections, and in cases of unexpected bioterror scenarios.

The serogroup B meningococcal outer membrane vesicle-based vaccine 4CMenB induces cross-species protection against Neisseria gonorrhoeae

There is a pressing need for a gonorrhea vaccine due to the high disease burden associated with gonococcal infections globally and the rapid evolution of antibiotic resistance in Neisseria gonorrhoeae (Ng). Current gonorrhea vaccine research is in the stages of antigen discovery and the identification of protective immune responses, and no vaccine has been tested in clinical trials in over 30 years. Recently, however, it was reported in a retrospective case-control study that vaccination of humans with a serogroup B Neisseria meningitidis (Nm) outer membrane vesicle (OMV) vaccine (MeNZB) was associated with reduced rates of gonorrhea. Here we directly tested the hypothesis that Nm OMVs induce cross-protection against gonorrhea in a well-characterized female mouse model of Ng genital tract infection. We found that immunization with the licensed Nm OMV-based vaccine 4CMenB (Bexsero) significantly accelerated clearance and reduced the Ng bacterial burden compared to administration of alum or PBS. Serum IgG and vaginal IgA and IgG that cross-reacted with Ng OMVs were induced by 4CMenB vaccination by either the subcutaneous or intraperitoneal routes. Antibodies from vaccinated mice recognized several Ng surface proteins, including PilQ, BamA, MtrE, NHBA (known to be recognized by humans), PorB, and Opa. Immune sera from both mice and humans recognized Ng PilQ and several proteins of similar apparent molecular weight, but MtrE was only recognized by mouse serum. Pooled sera from 4CMenB-immunized mice showed a 4-fold increase in serum bactericidal50 titers against the challenge strain; in contrast, no significant difference in bactericidal activity was detected when sera from 4CMenB-immunized and unimmunized subjects were compared. Our findings directly support epidemiological evidence that Nm OMVs confer cross-species protection against gonorrhea, and implicate several Ng surface antigens as potentially protective targets. Additionally, this study further defines the usefulness of murine infection model as a relevant experimental system for gonorrhea vaccine development.

Multispecies Interactions in Biofilms and Implications to Safety of Drinking Water Distribution System

In the aquatic environment, microorganisms are predominantly organized as biofilms. Biofilms are formed by the aggregation of microbial cells and are surrounded by a matrix of extracellular polymeric substances (EPS) secreted by the microbial cells. Biofilms are attached to various surfaces, such as the living tissues, indwelling medical devices, and piping of the industrial potable water system. Biofilms formed from a single species has been extensively studied. However, there is an increased research focus on multispecies biofilms in recent years. It is important to assess the microbial mechanisms underlying the regulation of multispecies biofilm formation to determine the drinking water microbial composition. These mechanisms contribute to the predominance of the best-adapted species in an aquatic environment. This review focuses on the interactions in the multispecies biofilms, such as coaggregation, co-metabolism, cross-species protection, jamming of quorum sensing, lateral gene transfer, synergism, and antagonism. Further, this review explores the dynamics and the factors favoring biofilm formation and pathogen transmission within the drinking water distribution systems. The understanding of the physiology and biodiversity of microbial species in the biofilm may aid in the development of novel biofilm control and drinking water disinfection processes.

Function-guided selection of midgut antigens from Ornithodoros erraticus ticks and an evaluation of their protective efficacy in rabbits

The identification of candidate protective antigens for the development of tick vaccines may be approached by selecting antigen candidates that play key biological functions. Tick midgut proteins that play essential functions in tick survival and disease transmission are upregulated in response to blood feeding and digestion. In this study, Ornithodoros erraticus midgut transcriptomic and proteomic data upon feeding were inspected to select functionally relevant antigens to be assessed as vaccine candidate antigens. For this, we primarily focused on proteins with relevant biological functions in key physiological processes for ticks and tick-host-pathogen interactions. Later, we used additional criteria based on overexpression after feeding, predicted antigenicity and cellular localisation, resulting in the selection of four theoretical candidates, two aquaporins (OeAQP, OeAQP1), one ABC transporter (OeABC) and one selenoprotein T (OeSEL). Rabbit vaccination with synthetic immunogenic peptides designed from the extracellular antigenic regions of the selected candidates induced humoral responses that reduced tick feeding and reproduction performance. Both AQPs and OeSEL demonstrated significant protection efficacy against the homologous species O. erraticus, but lower non-significant cross-species protection against Ornithodoros moubata. Conversely, OeABC showed no protection against the homologous species O. erraticus, but significant cross-species protection against O. moubata. These results are the first demonstration of the protective potential of argasid aquaporins, suggesting that they might be included in vaccines for the control of multiple tick species. Additionally, these results also unveiled two novel protective antigens from argasid ticks, OeABC and OeSEL, belonging to functional protein families that have never been explored as a source of vaccine candidates and are deserving of further studies. Finally, our data add value to the midgut as a protective candidate antigen source in argasids for the control of tick infestations.

Controlling Liquid–Liquid Phase Separation of Cold-Adapted Crystallin Proteins from the Antarctic Toothfish

Liquid–liquid phase separation (LLPS) of proteins is important to a variety of biological processes both functional and deleterious, including the formation of membraneless organelles, molecular condensations that sequester or release molecules in response to stimuli, and the early stages of disease-related protein aggregation. In the protein-rich, crowded environment of the eye lens, LLPS manifests as cold cataract. We characterize the LLPS behavior of six structural γ-crystallins from the eye lens of the Antarctic toothfish Dissostichus mawsoni, whose intact lenses resist cold cataract in subzero waters. Phase separation of these proteins is not strongly correlated with thermal stability, aggregation propensity, or cross-species chaperone protection from heat denaturation. Instead, LLPS is driven by protein–protein interactions involving charged residues. The critical temperature of the phase transition can be tuned over a wide temperature range by selective substitution of surface residues, suggesting general principles for controlling this phenomenon, even in compactly folded proteins.

Comparison of the nine polymorphic membrane proteins of Chlamydia trachomatis for their ability to induce protective immune responses in mice against a C. muridarum challenge

ObjectivesTo test vaccines, formulated with novel antigens, to protect mice against Chlamydia infections. MethodsTo determine the ability of polymorphic membrane proteins (Pmps) to induce cross-species protective immune responses, recombinant fragments from all nine C. trachomatis serovar E Pmps were used to vaccinate BALB/c mice utilizing CpG-1826 and Montanide ISA 720 as adjuvants. C. muridarum recombinant MOMP and PBS, formulated with the same adjuvants, were used as positive and negative controls, respectively. Mice were challenged intranasally with 104 inclusion-forming units (IFU) of C. muridarum. Animals were weighed daily and at 10days post-challenge, they were euthanized, their lungs harvested, weighed and the number of chlamydial IFU counted. ResultsFollowing vaccination the nine Pmps elicited immune responses. Based on body weight changes, or number of IFU recovered from lungs, mice vaccinated with Pmp C, G or H were the best protected. For example, over the 10-day period, the negative control group vaccinated with PBS lost significantly more body weight than mice immunized with PmpC or G (P<0.05). C. muridarum MOMP vaccinated mice were better protected against body weight losses than any group immunized with Pmps. Also, the median number of IFU recovered from the lungs of mice vaccinated with PmpC (72×106) or PmpH (61×106) was significantly less than from mice immunized with PBS (620×106; P<0.05). As determined by the number of IFU, all Pmps elicited less protection than C. muridarum MOMP (0.078×106 IFU; P<0.05). ConclusionsThis is the first time PmpC has been shown to elicit cross-species protection against a respiratory challenge. Additional work with Pmps C, G and H is recommended to determine their ability to protect animal models against genital and ocular challenges.

Assessment of the Plasmodium falciparum Preerythrocytic Antigen UIS3 as a Potential Candidate for a Malaria Vaccine.

ABSTRACTEfforts are under way to improve the efficacy of subunit malaria vaccines through assessments of new adjuvants, vaccination platforms, and antigens. In this study, we further assessed the Plasmodium falciparum antigen upregulated in infective sporozoites 3 (PfUIS3) as a vaccine candidate. PfUIS3 was expressed in the viral vectors chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) and used to immunize mice in a prime-boost regimen. We previously demonstrated that this regimen could provide partial protection against challenge with chimeric P. berghei parasites expressing PfUIS3. We now show that ChAd63-MVA PfUIS3 can also provide partial cross-species protection against challenge with wild-type P. berghei parasites. We also show that PfUIS3-specific cellular memory responses could be recalled in human volunteers exposed to P. falciparum parasites in a controlled human malaria infection study. When ChAd63-MVA PfUIS3 was coadministered with the vaccine candidate P. falciparum thrombospondin-related adhesion protein (PfTRAP) expressed in the ChAd63-MVA system, there was no significant change in immunogenicity to either vaccine. However, when mice were challenged with double chimeric P. berghei-P. falciparum parasites expressing both PfUIS3 and PfTRAP, vaccine efficacy was improved to 100% sterile protection. This synergistic effect was evident only when the two vaccines were mixed and administered at the same site. We have therefore demonstrated that vaccination with PfUIS3 can induce a consistent delay in patent parasitemia across mouse strains and against chimeric parasites expressing PfUIS3 as well as wild-type P. berghei; when this vaccine is combined with another partially protective regimen (ChAd63-MVA PfTRAP), complete protection is induced.

Safety, immunogenicity, and cross-species protection of a plasmid DNA encoding Plasmodium falciparum SERA5 polypeptide, microbial epitopes and chemokine genes in mice and olive baboons.

Incorporation of biomolecular epitopes to malarial antigens should be explored in the development of strain-transcending malarial vaccines. The present study sought to determine safety, immunogenicity and cross-species efficacy ofPlasmodium falciparum serine repeat antigen 5 polypeptide co-expressed with epitopes of Bacille-Calmette Guerin (BCG), tetanus toxoid (TT) and a chemokine gene. Olive baboons and BALB/c mice were randomly assigned into vaccine and control groups. The vaccine group animals were primed and boosted twice with pIRES plasmids encoding the SERA5+ BCG+ TT alone, or with either CCL5 or CCL20 and the control group with pIRES plasmid vector backbone. Mice and baboons were challenged withP. berghei ANKA and P. knowlesi H strain parasites, respectively. Safety was determined by observing for injection sites reactogenicities, hematology and clinical chemistry. Parasitaemia and survivorship profiles were used to determine cross-species efficacy, and T cell phenotypes, Th1-, Th2-type, T-regulatory immune responses and antibody responses were assessed to determine vaccine immunogenicity. The pSeBCGTT plasmid DNA vaccines were safe and induced Th1-, Th2-type, and T-regulatory responses vaccinated animals showed enhanced CD4+ (P<0.01), CD 8+ T cells (P<0.001) activation and IgG anti-SE36 antibodies responses (P<0.001) at week 4 and 8 post vaccination compared to the control group. Vaccinated mice had a 31.45-68.69% cumulative parasite load reduction and 60% suppression in baboons (P<0.05) and enhanced survivorship (P<0.001) with no clinical signs of malaria compared to the control group. The results showed that the vaccines were safe, immunogenic and conferred partial cross-species protection.

Committing Leishmania vaccine to memory

A Leishmania protein vaccine elicited immune responses and mediated strong cross-species protection.

Identification of broadly conserved cross-species protective Leishmania antigen and its responding CD4+ T cells.

There is currently no clinically effective vaccine against leishmaniasis because of poor understanding of the antigens that elicit dominant T cell immunity. Using proteomics and cellular immunology, we identified a dominant naturally processed peptide (PEPCK335-351) derived from Leishmania glycosomal phosphoenolpyruvate carboxykinase (PEPCK). PEPCK was conserved in all pathogenic Leishmania, expressed in glycosomes of promastigotes and amastigotes, and elicited strong CD4(+) T cell responses in infected mice and humans. I-A(b)-PEPCK335-351 tetramer identified protective Leishmania-specific CD4(+) T cells at a clonal level, which comprised ~20% of all Leishmania-reactive CD4(+) T cells at the peak of infection. PEPCK335-351-specific CD4(+) T cells were oligoclonal in their T cell receptor usage, produced polyfunctional cytokines (interleukin-2, interferon-γ, and tumor necrosis factor), and underwent expansion, effector activities, contraction, and stable maintenance after lesion resolution. Vaccination with PEPCK peptide, DNA expressing full-length PEPCK, or rPEPCK induced strong durable cross-species protection in both resistant and susceptible mice. The effectiveness and durability of protection in vaccinated mice support the development of a broadly cross-species protective vaccine against different forms of leishmaniasis by targeting PEPCK.

Cross-species protection: Schistosoma mansoni Sm-p80 vaccine confers protection against Schistosoma haematobium in hamsters and baboons

The ability of the Schistosoma mansoni antigen, Sm-p80, to provide cross-species protection against Schistosoma haematobium challenge was evaluated in hamster and baboon models. Pronounced reduction in worm burden (48%) and in tissue egg load (64%) was observed in hamsters vaccinated with recombinant Sm-p80 admixed with glucopyranosyl lipid adjuvant-stable emulsion (GLA-SE). Similarly, in baboons, the Sm-p80/GLA-SE vaccine produced a 25% reduction in S. haematobium adult worms and decreased the egg load in the urinary bladder by 64%. A 40% and 53% reduction in fecal and urine egg output, respectively, was observed in vaccinated baboons. A balanced pro-inflammatory (Th17 and Th1) and Th2 type of response was generated after vaccination and appears indicative of augmented prophylactic efficacy. These data on cross-species protection coupled with the prophylactic, therapeutic and antifecundity efficacy against the homologous parasite, S. mansoni, reinforces Sm-p80 as a promising vaccine candidate. It is currently being prepared for GMP-compliant manufacture and for further pre-clinical development leading to human clinical trials. These results solidify the expectation that the Sm-p80 vaccine will provide relief for both the intestinal and the urinary schistosomiasis and thus will be greatly beneficial in reducing the overall burden of schistosomiasis.

Intranasal Vaccination with Chlamydia pneumoniae Induces Cross-Species Immunity against Genital Chlamydia muridarum Challenge in Mice

Chlamydia trachomatis is the most common bacterial sexually transmitted disease in the world and specifically in the United States, with the highest incidence in age-groups 14–19 years. In a subset of females, the C. trachomatis genital infection leads to serious pathological sequelae including pelvic inflammatory disease, ectopic pregnancy, and infertility. Chlamydia pneumoniae, another member of the same genus, is a common cause of community acquired respiratory infection with significant number of children aged 5–14 yr displaying sero-conversion. Since these bacteriae share several antigenic determinants, we evaluated whether intranasal immunization with live C. pneumoniae (1×106 inclusion forming units; IFU) in 5 week old female C57BL/6 mice would induce cross-species protection against subsequent intravaginal challenge with Chlamydia muridarum (5×104 IFU), which causes a similar genital infection and pathology in mice as C. trachomatis in humans. Mice vaccinated intranasally with live C. pneumoniae, but not mock (PBS) immunized animals, displayed high levels of splenic cellular antigen-specific IFN-γ production and serum antibody response against C. muridarum and C. trachomatis. Mice vaccinated with C. pneumoniae displayed a significant reduction in the vaginal C. muridarum shedding as early as day 12 after secondary i.vag. challenge compared to PBS (mock) immunized mice. At day 19 after C. muridarum challenge, 100% of C. pneumoniae vaccinated mice had cleared the infection compared to none (0%) of the mock immunized mice, which cleared the infection by day 27. At day 80 after C. muridarum challenge, C. pneumoniae vaccinated mice displayed a significant reduction in the incidence (50%) and degree of hydrosalpinx compared to mock immunized animals (100%). These results suggest that respiratory C. pneumoniae infection induces accelerated chlamydial clearance and reduction of oviduct pathology following genital C. muridarum challenge, and may have important implications to the C. trachomatis-induced reproductive disease in humans.

Lack of associations of α+-thalassemia with the risk of Plasmodium falciparum and Plasmodium vivax infection and disease in a cohort of children aged 3–21 months from Papua New Guinea

Despite consistent evidence of a protective effect of α+-thalassemia against severe Plasmodium falciparum disease, the mechanisms underlying this protection remain unknown. An increase in risk of Plasmodium vivax malaria in early childhood resulting in a cross-species protection against severe P. falciparum malaria has been proposed as a possible mechanism in Melanesian children. The association of α+-thalassemia genotypes with a risk of P. falciparum and P. vivax infection and uncomplicated illness was reassessed in a cohort of 1,112 Papua New Guinean children, followed from 3 to 21months of age. Three hundred and eighty-nine (35.0%) children were homozygous for α+-thalassemia (-α/-α), 506 (45.5%) heterozygous (αα/-α) and 217 (19.5%) homozygous for the wild-type allele. No significant differences in the incidence of P. falciparum (Pf) or P. vivax (Pv) malaria were observed between α+-thalassemia homozygote (Pf: incidence rate ratio (IRR)=1.13, CI95 (0.82, 1.56), P=0.45, Pv: IRR=1.15, CI95 (0.88, 1.50), P=0.31), heterozygote (Pf: IRR=0.98, CI95 (0.71, 1.34), P=0.93, Pv: IRR=1.14, CI95 (0.88, 1.48), P=0.33) and wild-type children. The prevalence of infection with either species did not differ between α+-thalassemia genotypes, although densities of P. vivax (but not of P. falciparum) infections were significantly higher in α+-thalassemia homozygote and heterozygote children. An excessive risk of moderate-to-severe anemia (Hb<8g/dl) was observed in α+-thalassemia homozygote children (IRR=1.54, CI95 (1.12, 2.11), P=0.008). This study therefore failed to confirm an increased risk of P. vivax or P. falciparum malaria in very young, α+-thalassemic children without significant levels of acquired immunity. This confirms the lack of protection by α+-thalassemia against uncomplicated P. falciparum and challenges the hypothesis of immunological cross-protection between P. falciparum and P. vivax as a mechanism underlying α+-thalassemia protection against severe P. falciparum disease in Melanesian children.

Exciting Developments in the Immunology of Fungal Infections

The last decade has brought significant advances in our understanding of antifungal immunity, which offer hope for the development of novel immunotherapeutics. In this commentary, we provide a snapshot of the protective innate and adaptive components of antifungal immunity and highlight several recent topics of interest, placing in context the three associated reviews in this issue of Cell Host & Microbe.