Unrelated Pathogens Research Articles

Bystander CD8 T cell memory responses partially protect mice against lethal vaginal HSV-2 challenge

Abstract Herpes Simplex Virus type-2 (HSV-2) infection is one of the most prevalent sexually transmitted infections, yet no vaccine is currently available. Detailed analysis of HSV-infected human tissue revealed tissue-resident CD8 T cells (TRM) limit the duration and severity of HSV-2 episodes. Interestingly, recent studies indicate that the sensing and alarming function of CD8 TRMs is not restricted to cognate antigen interaction, but CD8 TRM can mediate protection against antigenically unrelated pathogens, termed “bystander activation.” Here, we investigated if antigen non-specific CD8 T cells could provide some degree of protection in a bystander fashion in the context of HSV infection. To test this, we created antigen non-specific memory compartments through immunization of mice with Listeria expressing ovalbumin (OVA) (LM-OVA). Mice were then challenged with wild-type HSV-2 to assess the degree of bystander-mediated protection. Immunization with LM-OVA-delayed disease progression from lethal viral challenge, suggesting that bystander CD8 T cells may mediate protection despite the lack of antigen-specificity. Furthermore, we found early infiltration of antigen-non-specific CD8 T cells (OVA-specific) in the vaginal tract in the infection setting. Additionally, assessment of the memory CD8 compartment in human vaginal tissue upon in-vitro treatment with cytokines caused bystander activation of memory CD8 T cells. Finally, we found that in-vitro treatment of CD8 T cells with cytokines delayed disease progression and reduced viral burden upon adoptive transfer. Altogether, our findings suggest that local bystander-activation of CD8 memory T cells can participate in protection from HSV-2.

Functional analysis of the Nep1-like proteins from Plasmopara viticola

ABSTRACT Necrosis and ethylene-inducing peptide 1 (Nep1) -like proteins (NLP) are secreted by multiple taxonomically unrelated plant pathogens (bacteria, fungi, and oomycete) and are best known for inducing cell death and immune responses in dicotyledonous plants. A group of putative NLP genes from obligate biotrophic oomycete Plasmopara viticola were predicted by RNA-Seq in our previous study, but their activity has not been established. Therefore, we analyzed the P. viticola NLP (PvNLP) family and identified seven PvNLP genes. They all belong to type 1 NLP genes and form a P. viticola-specific cluster when compared with other pathogen NLP genes. The expression of PvNLPs was induced during early infection process and the expression patterns could be categorized into two groups. Agrobacterium tumefaciens-mediated transient expression assays revealed that only PvNLP7 was cytotoxic and could induce Phytophthora capsici resistance in Nicotiana benthamiana. Functional analysis showed that PvNLP4, PvNLP5, PvNLP7, and PvNLP10 significantly improved disease resistance of Arabidopsis thaliana to Hyaloperonospora arabidopsidis. Moreover, the four genes caused an inhibition of plant growth which is typically associated with enhanced immunity when over-expressed in Arabidopsis. Further research found that PvNLP7 could activate the expression of defense-related genes and its conserved NPP1 domain was critical for cell death- and immunity-inducing activity. This record of NLP genes from P. viticola showed a functional diversification, laying a foundation for further study on pathogenic mechanism of the devastating pathogen.

Recombinant BCG Expressing the Subunit 1 of Pertussis Toxin Induces Innate Immune Memory and Confers Protection against Non-Related Pathogens.

BCG has shown the ability to induce protection against unrelated pathogens, which likely depends on an immune mechanism known as innate immune memory or trained immunity. In this study, we evaluated the induction of innate memory by a recombinant BCG strain expressing the genetically detoxified S1 subunit of the pertussis toxin (rBCG-S1PT). In vitro pre-exposure of naïve murine macrophages to rBCG-S1PT increased their innate/inflammatory response (IL-6, TNF-α, and IL-10) to a subsequent challenge with unrelated pathogens, as compared to pre-exposure to wild-type BCG. Following LPS challenge, mice immunized with rBCG-S1PT produced higher levels of IFN-γ, while the release of other inflammatory cytokines was comparable to that measured after BCG immunization. SCID mice previously immunized with rBCG-S1PT and challenged with pathogenic Candida albicans displayed a similar survival curve as BCG-immunized mice but a lower CFU burden in the kidneys, suggesting an innate memory-dependent control of C. albicans infection. This study highlights the potential of recombinant BCG to increase innate immune memory and, ultimately, non-specific protection, more effectively than wild-type BCG. To our knowledge, this is the first report describing the potential of a recombinant BCG strain to strengthen innate immune memory responses.

Hepatitis B vaccine co-administration influences the heterologous effects of neonatal BCG vaccination in a sex-differential manner

IntroductionBacille Calmette-Guérin (BCG) and hepatitis B (HBV) vaccines are frequently given concomitantly at birth. Neonatal BCG vaccination induces off-target immunological effects. Whether HBV vaccine has immunomodulatory effects is unknown. As off-target effects might vary when vaccines are given simultaneously, this randomised controlled trial aimed to evaluate the influence of neonatal vaccination with BCG and/or HBV on heterologous immune responses. MethodsA total of 185 neonates in Australia were randomised to receive either neonatal BCG-Denmark vaccine, HBV vaccine, both (BCG + HBV group), or none (No vaccine group). In-vitro responses to heterologous stimulants were assessed 7 days after vaccination. The influence of (i) randomisation group and (ii) sex on interferon-gamma (IFN-γ), monocyte chemoattractant protein-1 (MCP-1), and tumour necrosis factor-alpha (TNF-α) responses was analysed using linear regression. ResultsOverall, BCG vaccination alone or with HBV co-administration reduced IFN-γ and MCP-1 responses to heterologous stimulants. HBV vaccination alone did not alter heterologous cytokine responses. In general, males produced more IFN-γ and TNF-α than females. We observed a sex-differential effect in relation to the influence of HBV co-administration on the effect of BCG on heterologous responses. Compared with males in the No vaccine group, males in the BCG + HBV group had lower IFN-γ and MCP-1 responses. In contrast, compared with females in the No vaccine group, females in the BCG group had higher IFN-γ response and lower MCP-1 responses. ConclusionNeonatal BCG vaccination resulted in lower cytokine responses to unrelated pathogens. HBV co-administration did not have a significant impact on responses overall but influenced the heterologous effects of neonatal BCG vaccination in a sex-differential manner.

Symptomic Mimicry Between SARS-CoV-2 and the Common Cold Complex

The recent changes in COVID-19 symptoms suggest convergent evolution of respiratory diseases. This process is analogous to the emergence of animal mimetic complexes and complements previously identified types of mimicry. A novel pathogen might go unnoticed or insufficiently counteracted if it resembles a disease that the host already faced on multiple occasions, which creates a selective pressure towards a typical symptomic phonotype. In short, the reason why so many unrelated pathogens cause similar symptoms may correspond to the reasons that drove the evolution of the ‘warning’ wasp-like colouration in various insect species.

Hypothetical Immunological and Immunogenetic Model of Heterogenous Effects of BCG Vaccination in SARS-CoV-2 Infections: BCG-induced Trained and Heterologous Immunity

Though SARS-CoV-2 infections are yet to be completely characterised in a host-pathogen interaction context, some of the mechanisms governing the interaction between the novel betacoronavirus and the human host, have been brought to light in satisfactory detail. Among the emerging evidence, postulates regarding potential benefits of innate immune memory and heterologous immunity have been put under discussion. Innate immune memory entails epigenetic reprogramming of innate immune cells caused by vaccination or infections, whereas heterologous immunity denotes cross-reactivity of T cells with unrelated epitopes and bystander CD8+ activation. Familiarization of the host immune system with a certain pathogen, educates monocytes, macrophages and other innate cells into phenotypes competent for combating unrelated pathogens. Indeed, the resolution at which non-specific innate immune memory occurs, is predominant at the level of enhanced cytokine secretion as a result of epigenetic alterations. One vaccine whose non-specific effects have been documented and harnessed in treating infections, cancer and autoimmunity, is the Bacillus Calmette–Guérin (BCG) vaccine currently used for immunization against pulmonary tuberculosis (TB). The BCG vaccine induces a diverse cytokine secretion profile in immunized subjects, which in turn may stimulate epigenetic changes mediated by immunoreceptor signalling. Herein, we provide a concise summarization of previous findings regarding the effects of the BCG vaccine on innate immune memory and heterologous immunity, supplemented with clinical evidence of the non-specific effects of this vaccine on non-mycobacterial infections, cancer and autoimmunity. This interpretative synthesis aims at providing a plausible immunological and immunogenetic model by which BCG vaccination may, in fact, be beneficial for the current efforts in combating COVID-19.

Intravenous administration of BCG protects mice against lethal SARS-CoV-2 challenge.

In addition to providing partial protection against pediatric tuberculosis, vaccination with bacille Calmette-Guérin (BCG) has been reported to confer nonspecific resistance to unrelated pulmonary pathogens, a phenomenon attributed to the induction of long-lasting alterations within the myeloid cell compartment. Here, we demonstrate that intravenous, but not subcutaneous, inoculation of BCG protects human-ACE2 transgenic mice against lethal challenge with SARS-CoV-2 (SCV2) and results in reduced viral loads in non-transgenic animals infected with an α variant. The observed increase in host resistance was associated with reductions in SCV2-induced tissue pathology, inflammatory cell recruitment, and cytokine production that multivariate analysis revealed as only partially related to diminished viral load. We propose that this protection stems from BCG-induced alterations in the composition and function of the pulmonary cellular compartment that impact the innate response to the virus and ensuing immunopathology. While intravenous BCG vaccination is not a clinically acceptable practice, our findings provide an experimental model for identifying mechanisms by which nonspecific stimulation of the pulmonary immune response promotes host resistance to SCV2 lethality.

Enteric pathogens induce tissue tolerance and prevent neuronal loss from subsequent infections

The enteric nervous system (ENS) controls several intestinal functions including motility and nutrient handling, which can be disrupted by infection-induced neuropathies or neuronal cell death. We investigated possible tolerance mechanisms preventing neuronal loss and disruption in gut motility after pathogen exposure. We found that following enteric infections, muscularis macrophages (MMs) acquire a tissue-protective phenotype that prevents neuronal loss, dysmotility, and maintains energy balance during subsequent challenge with unrelated pathogens. Bacteria-induced neuroprotection relied on activation of gut-projecting sympathetic neurons and signaling via β2-adrenergic receptors (β2AR) on MMs. In contrast, helminth-mediated neuroprotection was dependent on Tcells and systemic production of interleukin (IL)-4 and IL-13 by eosinophils, which induced arginase-expressing MMs that prevented neuronal loss from an unrelated infection located in a different intestinal region. Collectively, these data suggest that distinct enteric pathogens trigger a state of disease or tissue tolerance that preserves ENS number and functionality.

Recent Progress in Shigella and Burkholderia pseudomallei Vaccines.

Significant advancement has been made in the development of vaccines against bacterial pathogens. However, several roadblocks have been found during the evaluation of vaccines against intracellular bacterial pathogens. Therefore, new lessons could be learned from different vaccines developed against unrelated intracellular pathogens. Bacillary dysentery and melioidosis are important causes of morbidity and mortality in developing nations, which are caused by the intracellular bacteria Shigella and Burkholderia pseudomallei, respectively. Although the mechanisms of bacterial infection, dissemination, and route of infection do not provide clues about the commonalities of the pathogenic infectious processes of these bacteria, a wide variety of vaccine platforms recently evaluated suggest that in addition to the stimulation of antibodies, identifying protective antigens and inducing T cell responses are some additional required elements to induce effective protection. In this review, we perform a comparative evaluation of recent candidate vaccines used to combat these two infectious agents, emphasizing the common strategies that can help investigators advance effective and protective vaccines to clinical trials.

Repurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy of Mycobacterium tuberculosis and Salmonella enterica infections

The persistent increase of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) infections negatively impacts Tuberculosis treatment outcomes. Host-directed therapies (HDT) pose an complementing strategy, particularly since Mtb is highly successful in evading host-defense by manipulating host-signaling pathways. Here, we screened a library containing autophagy-modulating compounds for their ability to inhibit intracellular Mtb-bacteria. Several active compounds were identified, including two drugs of the diphenylbutylpiperidine-class, Fluspirilene and Pimozide, commonly used as antipsychotics. Both molecules inhibited intracellular Mtb in pro- as well as anti-inflammatory primary human macrophages in a host-directed manner and synergized with conventional anti-bacterials. Importantly, these inhibitory effects extended to MDR-Mtb strains and the unrelated intracellular pathogen, Salmonella enterica serovar Typhimurium (Stm). Mechanistically Fluspirilene and Pimozide were shown to regulate autophagy and alter the lysosomal response, partly correlating with increased bacterial localization to autophago(lyso)somes. Pimozide’s and Fluspirilene’s efficacy was inhibited by antioxidants, suggesting involvement of the oxidative-stress response in Mtb growth control. Furthermore, Fluspirilene and especially Pimozide counteracted Mtb-induced STAT5 phosphorylation, thereby reducing Mtb phagosome-localized CISH that promotes phagosomal acidification. In conclusion, two approved antipsychotic drugs, Pimozide and Fluspirilene, constitute highly promising and rapidly translatable candidates for HDT against Mtb and Stm and act by modulating the autophagic/lysosomal response by multiple mechanisms.

Pulmonary infection induces persistent, pathogen-specific lipidomic changes influencing trained immunity

SummaryResolution of infection results in development of trained innate immunity which is typically beneficial for defense against unrelated secondary infection. Epigenetic changes including modification of histones via binding of various polar metabolites underlie the establishment of trained innate immunity. Therefore, host metabolism and this response are intimately linked. However, little is known regarding the influence of lipids on the development and function of trained immunity. Utilizing two models of pulmonary bacterial infection combined with multi-omic approaches, we identified persistent, pathogen-specific changes to the lung lipidome that correlated with differences in the trained immune response against a third unrelated pathogen. Further, we establish the specific cellular populations in the lung that contribute to this altered lipidome. Together these results expand our understanding of the pulmonary trained innate immune response and the contributions of host lipids in informing that response.

Immunodominant Cytomegalovirus Epitopes Suppress Subdominant Epitopes in the Generation of High-Avidity CD8 T Cells

CD8+ T-cell responses to pathogens are directed against infected cells that present pathogen-encoded peptides on MHC class-I molecules. Although natural responses are polyclonal, the spectrum of peptides that qualify for epitopes is remarkably small even for pathogens with high coding capacity. Among those few that are successful at all, a hierarchy exists in the magnitude of the response that they elicit in terms of numbers of CD8+ T cells generated. This led to a classification into immunodominant and non-immunodominant or subordinate epitopes, IDEs and non-IDEs, respectively. IDEs are favored in the design of vaccines and are chosen for CD8+ T-cell immunotherapy. Using murine cytomegalovirus as a model, we provide evidence to conclude that epitope hierarchy reflects competition on the level of antigen recognition. Notably, high-avidity cells specific for non-IDEs were found to expand only when IDEs were deleted. This may be a host’s back-up strategy to avoid viral immune escape through antigenic drift caused by IDE mutations. Importantly, our results are relevant for the design of vaccines based on cytomegaloviruses as vectors to generate high-avidity CD8+ T-cell memory specific for unrelated pathogens or tumors. We propose the deletion of vector-encoded IDEs to avoid the suppression of epitopes of the vaccine target.

Human Newborn Monocytes Demonstrate Distinct BCG-Induced Primary and Trained Innate Cytokine Production and Metabolic Activation In Vitro.

BackgroundNewborns exhibit distinct immune responses and are at high risk of infection. Neonatal immunization with BCG, the live attenuated vaccine against tuberculosis (TB), is associated with broad protection against a range of unrelated pathogens, possibly reflecting vaccine-induced training of innate immune cells (“innate memory”). However, little is known regarding the impact of age on BCG-induced innate responses.ObjectiveEstablish an age-specific human monocyte in vitro training platform to characterize and compare BCG-induced primary and memory cytokine responses and immunometabolic shifts.Design/MethodsHuman neonatal and adult CD33-selected monocytes were stimulated for 24h with RPMI (control) or BCG (Danish strain) in 10% autologous serum, washed and cultured for 5 additional days, prior to re-stimulation with the TLR4 agonist LPS for another 24h. Supernatants were collected at Day 1 (D1) to measure primary innate responses and at Day 7 (D7) to assess memory innate responses by ELISA and multiplex cytokine and chemokine assays. Lactate, a signature metabolite increased during trained immunity, was measured by colorimetric assay.ResultsCytokine production by human monocytes differed significantly by age at D1 (primary, BCG 1:750 and 1:100 vol/vol, p<0.0001) and D7 (innate memory response, BCG 1:100 vol/vol, p<0.05). Compared to RPMI control, newborn monocytes demonstrated greater TNF (1:100, 1:10 vol/vol, p<0.01) and IL-12p40 (1:100 vol/vol, p<0.05) production than adult monocytes (1:100, p<0.05). At D7, while BCG-trained adult monocytes, as previously reported, demonstrated enhanced LPS-induced TNF production, BCG-trained newborn monocytes demonstrated tolerization, as evidenced by significantly diminished subsequent LPS-induced TNF (RPMI vs. BCG 1:10, p <0.01), IL-10 and CCL5 production (p<0.05). With the exception of IL-1RA production by newborn monocytes, BCG-induced monocyte production of D1 cytokines/chemokines was inversely correlated with D7 LPS-induced TNF in both age groups (p<0.0001). Compared to BCG-trained adult monocytes, newborn monocytes demonstrated markedly impaired BCG-induced production of lactate, a metabolite implicated in immune training in adults.ConclusionsBCG-induced human monocyte primary- and memory-innate cytokine responses were age-dependent and accompanied by distinct immunometabolic shifts that impact both glycolysis and training. Our results suggest that immune ontogeny may shape innate responses to live attenuated vaccines, suggesting age-specific approaches to leverage innate training for broad protection against infection.

Rapid cell cycling of both circulating and resident memory CD8+ T cells driven by common gamma chain-dependent cytokines

Abstract Diverse populations of resident leukocytes live and self-renew within the tissues of the body, but the mechanisms controlling their proliferation are poorly understood. Among these populations are many memory CD8+ T cells, which are found throughout the body and can locally control reinfection. A poor ability of vaccines to elicit stable and appropriate tissue-resident CD8+ T cell populations has likely contributed to long-standing challenges in vaccinating against several important pathogens. The factors required to support TRM proliferation in homeostasis are not well understood. We propose that proliferating TRMs flexibly use the available members of the common gamma chain-(γC)-dependent cytokine family to persist as bystanders during other immune responses. We have found that many γC-dependent cytokines can mediate cell-intrinsic signaling to drive proliferation of both circulating and resident memory CD8+ T cells of known antigen specificities without cognate antigen. Via transcriptional analysis of resting and in vivo cytokine-stimulated TRMs, we are elucidating downstream signaling and the gene expression signature of cytokine-driven TRM proliferation. We have also found that memory CD8+ T cells proliferate similarly in response to exogenous cytokines or unrelated pathogens, consistent with pathogen-elicited γC-dependent cytokine signals driving memory CD8+ T cell proliferation. These data support the concept that TRMs use γC-dependent cytokines produced during infections to support enhanced proliferation, likely to promote their maintenance. Our findings may lead to novel methods to therapeutically enhance TRM immunity.

Bystander CD8 T cell memory responses partially protect mice against lethal vaginal HSV-2 challenge

Abstract Herpes Simplex Virus type-2 (HSV-2) infection is one of the most prevalent sexually transmitted diseases, yet no vaccine is currently available. Detailed analysis of HSV-infected human tissue revealed tissue-resident CD8 T cells (TRM) limit the duration and severity of HSV-2 episodes. Interestingly, recent studies reveal that the sensing and alarming function of CD8 TRMs is not restricted to cognate antigen interaction, but CD8 TRM can mediate protection against antigenically unrelated pathogens, termed “bystander activation.” Here, we extended our findings to determine if antigen non-specific CD8 T cells could provide some degree of protection in a bystander fashion in the context of HSV infection. To test this, we created antigen non-specific memory compartments through immunization of mice with Listeria expressing ovalbumin (OVA) (LM-OVA). Mice were then challenged with wild-type HSV-2 to assess the degree of vaccine-mediated protection. Immunization with LM- OVA-induced intermediate protection from lethal viral challenge, suggesting that bystander CD8 T cells (BA-CTL) may mediate protection despite the absence of antigen-specificity. The bystander functionality could be context-dependent, and the unregulated expansion of these cells can be damaging to the host. A potential explanation of BA-CTL regulation is via the involvement of regulatory T cells (Tregs), in the absence of Treg-mediated regulation, massive expansion of BA-CTLs can be predicted. On the contrary, we found depletion of Tregs resulted in significantly fewer BA- CTLs in the vaginal tract on days 2 and 6 post-HSV-2 challenge. Hence how these cells maintain the delicate balance of protection against pathology necessitates further investigation.

CMV Status Drives Distinct Trajectories of CD4+ T Cell Differentiation.

Cytomegalovirus (CMV) is one of the most commonly recognized opportunistic pathogens and remains the most influential known parameter in shaping an individual’s immune system. As such, T cells induced by CMV infection could have a long-term impact on subsequent immune responses. Accumulating evidence indicates that memory T cells developed during past bacterial and viral infection can cross-react with unrelated pathogens, including transplant antigens, and can alter responses to de novo infections, vaccines, cancers, or rejection. Therefore, careful examination of T cell responses elicited by CMV is warranted to understand their potentially beneficial or harmful roles in future major immune events. Our detailed exploration of the distribution, phenotype, TCR repertoire and transcriptome of CD4+ T cells within CMV seropositive healthy individuals using high-dimensional flow cytometry and single cell multi-omics sequencing reveals that CMV seropositivity has highly significant age-independent effects, leading to a reduction in CD4+ naïve T cells and an expansion of CD4+ effector memory T cells and CD45RA+ effector memory T cells. These induced CD4+ effector memory T cells undergo a specific differentiation trajectory resulting in a subpopulation of CD57+CD27-CD28-CD244+ CD4+ T cells with cytotoxic function and TCR oligoclonality for optimal controlled coexistence with cytomegalovirus. Through gene set enrichment analysis, we found that this subpopulation is similar to virus-specific CD8+ T cells and T cells that mediate acute rejection in patients using tacrolimus and belatacept, a selective costimulation blocker. Together, these data suggest that memory CD4+ T cells induced by cytomegalovirus are formed via a distinct differentiation program to acquire cytotoxic function and can be potentially detrimental to transplant patients adopting costimulation blockade immunosuppressive regimen.

Advances in the development of Salmonella-based vaccine strategies for protection against Salmonellosis in humans.

Salmonella spp. are important human pathogens globally causing millions of cases of typhoid fever and non‐typhoidal salmonellosis annually. There are only a few vaccines licensed for use in humans which all target Salmonella enterica serovar Typhi. Vaccine development is hampered by antigenic diversity between the thousands of serovars capable of causing infection in humans. However, a number of attenuated candidate vaccine strains are currently being developed. As facultative intracellular pathogens with multiple systems for transporting effector proteins to host cells, attenuated Salmonella strains can also serve as ideal tools for the delivery of foreign antigens to create multivalent live carrier vaccines for simultaneous immunization against several unrelated pathogens. Further, the ease with which Salmonella can be genetically modified and the extensive knowledge of the virulence mechanisms of this pathogen means that this bacterium has often served as a model organism to test new approaches. In this review we focus on (1) recent advances in live attenuated Salmonella vaccine development, (2) improvements in expression of foreign antigens in carrier vaccines and (3) adaptation of attenuated strains as sources of purified antigens and vesicles that can be used for subunit and conjugate vaccines or together with attenuated vaccine strains in heterologous prime‐boosting immunization strategies. These advances have led to the development of new vaccines against Salmonella which have or will soon be tested in clinical trials.

BCG Vaccination Program Mitigates COVID19 Related Mortality: A Reality Check.

Since its origin in the Wuhan province of China in December 2019, Coronavirus Disease 19 (COVID-19) has spread to most parts of the world and has infected millions of people. However, the significant variability in the mortality rate across the world indicates some underlying factors, especially the immunity factors that may have a potential role in this variability. One such factor that is being discussed and tested is the Bacillus Calmette-Guerin (BCG) vaccine. The available evidence suggests that BCG vaccination provides broad protection against respiratory infections as well as other infections. Therefore, BCG may prove to be a barrier for COVID-19 infection and may offer a ray of hope. In this review, we contrasted BCG vaccination program with COVID-19 mortality and analyzed trained immunity and cross protection against unrelated pathogens due to BCG vaccination. On analyzing the available data, we observed that countries without universal BCG vaccination policy are severely affected, while countries having universal BCG policies are less affected. Based on these data, we propose that the SARS-CoV-2 related qualified immunity, cross protection against unrelated pathogens and COVID-19 impact variations could be partly explained by the different national policies regarding BCG childhood vaccination. The combination of reduced morbidity and mortality may make BCG vaccination a potential new tool in the fight against COVID-19.

Can existing unrelated vaccines boost a COVID-19 vaccine prime?

Can existing unrelated vaccines boost a COVID-19 vaccine prime?

Live attenuated Bordetella pertussis vaccine candidate BPZE1 transiently protects against lethal pneumococcal disease in mice

BPZE1 is a live attenuated vaccine against infection by Bordetella pertussis, the causative agent of whooping cough. It was previously shown that BPZE1 provides heterologous protection in mouse models of disease caused by unrelated pathogens, such as influenza virus and respiratory syncytial virus. Protection was also observed in mouse models of asthma and contact dermatitis. In this study, we demonstrate that BPZE1 also displays protection against an unrelated bacterial pathogen in a mouse model of invasive pneumococcal disease mediated by Streptococcus pneumoniae. While a single administration of BPZE1 provided no protection, two doses of 106 colony-forming units of BPZE1 given in a three-week interval protected against mortality, lung colonization and dissemination in both BALB/c and C57BL/6 mice. Unlike for the previously reported influenza challenge model, protection was short-lived, and waned within days after booster vaccination. Formaldehyde-killed BPZE1 protected only when administered following a live prime, indicating that priming requires live BPZE1 for protection. Protection against mortality was directly linked to substantially decreased bacterial dissemination in the blood and was lost in MyD88 knock-out mice, demonstrating the role of the innate immune system in the mechanism of protection. This is the first report on a heterologous protective effect of the live BPZE1 vaccine candidate against an unrelated bacterial infection.