Potentiating Lung Mucosal Immunity Through Intranasal Vaccination

Yearly administration of influenza vaccines is our best available tool for controlling influenza virus spread. However, both practical and immunological factors sometimes result in sub-optimal vaccine efficacy. The call for improved, or even universal, influenza vaccines within the field has led to development of pre-clinical and clinical vaccine candidates that aim to address limitations of current influenza vaccine approaches. Here, we consider the route of immunization as a critical factor in eliciting tissue resident memory (Trm) populations that are not a target of current licensed intramuscular vaccines. Intranasal vaccination has the potential to boost tissue resident B and T cell populations that reside within specific niches of the upper and lower respiratory tract. Within these niches, Trm cells are poised to respond rapidly to pathogen re-encounter by nature of their anatomic localization and their ability to rapidly deliver anti-pathogen effector functions. Unique features of mucosal immunity in the upper and lower respiratory tracts suggest that antigen localized to these regions is required for the elicitation of protective B and T cell immunity at these sites and will need to be considered as an important attribute of a rationally designed intranasal vaccine. Finally, we discuss outstanding questions and areas of future inquiry in the field of lung mucosal immunity.

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Effect of an adenovirus-vectored universal influenza virus vaccine on pulmonary pathophysiology in a mouse model

Journal of Virology ◽

10.1128/jvi.02359-20 ◽

2021 ◽

Author(s):

Santosh Dhakal ◽

Jeffrey Loube ◽

Julia A. Misplon ◽

Chia-Yun Lo ◽

Patrick Creisher ◽

...

Keyword(s):

Influenza Virus ◽

T Cell ◽

Pulmonary Inflammation ◽

T Cell Responses ◽

Cd8 T Cell ◽

T Cell Immunity ◽

Influenza Vaccines ◽

Cell Responses ◽

Cell Immunity ◽

Universal Influenza Vaccine

Current influenza vaccines, live-attenuated or inactivated, do not protect against antigenically novel influenza A viruses (IAVs) of pandemic potential, which has driven interest in development of universal influenza vaccines. Universal influenza vaccine candidates targeting highly conserved antigens of IAV nucleoprotein (NP) are promising as vaccines that induce T cell immunity, but concerns have been raised about the safety of inducing robust CD8 T cell responses in the lungs. Using a mouse model, we systematically evaluated effects of recombinant adenovirus vectors (rAd) expressing IAV NP (A/NP-rAd) or influenza B virus (IBV) NP (B/NP-rAd) on pulmonary inflammation and function after vaccination and following live IAV challenge. After A/NP-rAd or B/NP-rAd vaccination, female mice exhibited robust systemic and pulmonary vaccine-specific B cell and T cell responses and experienced no morbidity (e.g., body mass loss). Both in vivo pulmonary function testing and lung histopathology scoring revealed minimal adverse effects of intranasal rAd vaccination compared with unvaccinated mice. After IAV challenge, A/NP-rAd vaccinated mice experienced significantly less morbidity, had lower pulmonary virus titers, and developed less pulmonary inflammation than unvaccinated or B/NP-rAd vaccinated mice. Based on analysis of pulmonary physiology using detailed testing not previously applied to the question of T cell damage, mice protected by vaccination also had better lung function than controls. Results provide evidence that in this model, adenoviral universal influenza vaccine does not damage pulmonary tissue. In addition, adaptive immunity, in particular T-cell immunity in the lungs, does not cause damage when restimulated, but instead mitigates pulmonary damage following IAV infection. Importance: Respiratory viruses can emerge and spread rapidly, before vaccines are available. It would be a tremendous advance to use vaccines that protect against whole categories of viruses, such as universal influenza vaccines, without the need to predict which virus will emerge. Nucleoprotein (NP) of influenza virus provides a target conserved among strains and is a dominant T-cell target. In animals, vaccination to NP generates powerful T cell immunity and long-lasting protection against diverse influenza strains. Concerns have been raised, but not evaluated experimentally, that potent local T-cell responses might damage the lungs. We analyzed lung function in detail in the setting of such a vaccination. Despite CD8 T-cell responses in the lungs, lungs were not damaged and functioned normally after vaccination alone and were protected upon subsequent infection. This precedent provides important support for vaccines based on T-cell-mediated protection, currently being considered for both influenza and SARS-CoV-2 vaccines.

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Cytotoxic T-cell immunity as a target for influenza vaccines

The Lancet Infectious Diseases ◽

10.1016/s1473-3099(06)70443-1 ◽

2006 ◽

Vol 6 (5) ◽

pp. 255-256 ◽

Cited By ~ 13

Author(s):

Arno Müllbacher ◽

Mario Lobigs ◽

Mohammed Alsharifi ◽

Matthias Regner

Keyword(s):

T Cell ◽

T Cell Immunity ◽

Influenza Vaccines ◽

Cytotoxic T Cell ◽

Cell Immunity

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Intranasal Vaccination With Multiple Virulence Factors Promotes Mucosal Clearance of Streptococcus suis Across Serotypes and Protects Against Meningitis in Mice

The Journal of Infectious Diseases ◽

10.1093/infdis/jiz352 ◽

2019 ◽

Vol 220 (10) ◽

pp. 1679-1687 ◽

Cited By ~ 1

Author(s):

Xinxin Xing ◽

Shuai Bi ◽

Xin Fan ◽

Meilin Jin ◽

Wenjun Liu ◽

...

Keyword(s):

T Cell ◽

Virulence Factors ◽

Mucosal Immunity ◽

Natural Habitat ◽

Streptococcus Suis ◽

Critical Events ◽

Cell Responses ◽

Mucosal Site ◽

Intranasal Vaccine ◽

Suis Serotype

Abstract Background Streptococcus suis is an emerging zoonotic agent. Its natural habitat is the tonsils, which are the main portals of S. suis entry into the bloodstream of pigs. The remarkable variability of the bacteria and complex pathogenic mechanisms make the development of a vaccine a difficult task. Method Five conserved virulence factors involved in critical events of S. suis pathogenesis were combined and used as an intranasal vaccine (V5). The effect of V5 was investigated with intranasal and systemic challenge models. Results V5 induced antibody and T-cell responses at the mucosal site and systemically. The immunity promoted clearance of S. suis from the nasopharynx independent of S. suis serotypes and reduced lethality after systemic challenge with S. suis serotype 2. Moreover, mice that survived sepsis from intravenous infection developed meningitis, whereas none of these mice showed neuropathological symptoms after V5 receipt. Conclusion Intranasal immunization with multiple conserved virulence factors decreases S. suis colonization at the nasopharynx across serotypes and inhibits the dissemination of the bacteria in the host. The protective mucosal immunity effects would potentially reduce the S. suis reservoir and prevent S. suis disease in pigs.

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SARS-CoV-2 T cell immunity: Specificity, function, durability, and role in protection

Science Immunology ◽

10.1126/sciimmunol.abd6160 ◽

2020 ◽

Vol 5 (49) ◽

pp. eabd6160 ◽

Cited By ~ 42

Author(s):

Daniel M. Altmann ◽

Rosemary J. Boyton

Keyword(s):

T Cell ◽

Standardized Testing ◽

Protective Immunity ◽

Population Level ◽

T Cell Immunity ◽

T Cell Memory ◽

Clear Understanding ◽

Testing Methods ◽

Effector Functions ◽

Cell Immunity

In efforts to synthesize a clear understanding of SARS-CoV-2 protective immunity, antibody analysis has been paralleled by T cell studies across asymptomatic, mild and severe COVID-19. Defining CD4 and CD8 effector functions in protection is important considering that antibody responses appear short-lived and T cell memory is potentially more durable. To fully understand population level immunity, screening for both antibody and T cell immunity using standardized testing methods would be beneficial.

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Robust and Functional Immunity up to 9 months after SARS-CoV-2 infection: a Southeast Asian longitudinal cohort

10.1101/2021.08.12.455901 ◽

2021 ◽

Author(s):

Hoa My Thi Vo ◽

Alvino Maestri ◽

Sokchea Lay ◽

Sotheary Sann ◽

Nisa Ya ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

B Cells ◽

Developed Countries ◽

T Cell Response ◽

Least Developed Countries ◽

Humoral And Cellular Immunity ◽

Effector Functions ◽

Cell Immunity

Assessing the duration of humoral and cellular immunity remains key to overcome the current SARS-CoV-2 pandemic, especially in understudied populations in least developed countries. Sixty-four Cambodian individuals with laboratory-confirmed infection with asymptomatic or mild/moderate clinical presentation were evaluated for humoral immune response to the viral spike protein and antibody effector functions during acute phase of infection and at 6-9 months follow-up. Antigen-specific B cells, CD4+ and CD8+ T cells were characterized, and T cells were interrogated for functionality at late convalescence. Anti-spike (S) antibody titers decreased over time, but effector functions mediated by S-specific antibodies remained stable. S- and nucleocapsid (N)-specific B cells could be detected in late convalescence in the activated memory B cell compartment and are mostly IgG+. CD4+ and CD8+ T cell immunity was maintained to S and membrane (M) protein. Asymptomatic infection resulted in decreased ADCC and frequency of SARS-CoV-2-specific CD4+ T cells at late convalescence. Whereas anti-S antibodies correlated with S-specific B cells, there was no correlation between T cell response and humoral immunity. Hence, all aspects of a protective immune response are maintained up to nine months after SARS-CoV-2 infection in the absence of re-infection.

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Heterosubtypic T-Cell Immunity to Influenza in Humans: Challenges for Universal T-Cell Influenza Vaccines

Frontiers in Immunology ◽

10.3389/fimmu.2016.00195 ◽

2016 ◽

Vol 7 ◽

Cited By ~ 47

Author(s):

Saranya Sridhar

Keyword(s):

T Cell ◽

T Cell Immunity ◽

Influenza Vaccines ◽

Cell Immunity

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OP40 A core transferable microbiota in responders to faecal microbiota transplant for ulcerative colitis shape mucosal T-cell immunity

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.039 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S040-S041

Author(s):

L Gogokhia ◽

S Lima ◽

M Viladomiu ◽

Y Gerardin ◽

C Crawford ◽

...

Keyword(s):

T Cell ◽

Clinical Response ◽

Mouse Models ◽

Mucosal Immunity ◽

Strain Level ◽

Metagenomic Sequencing ◽

Faecal Microbiota ◽

Independent Manner ◽

Cell Immunity ◽

Faecal Samples

Abstract Background Biologic therapy has significantly improved treatment for UC, but nearly two-thirds of patients attenuate the response. Additional therapeutic modalities are therefore needed to address the underlying pathophysiology of UC. Faecal microbiota transplant (FMT) is an emerging therapy for the treatment of UC, but several randomised controlled trials have shown variable efficacy of FMT, and the microbial mechanisms responsible for clinical response are not well understood. Therefore, using samples from our pilot FMT study (Jacob, V, et al. Inflamm. Bowel Dis. 2017), we aim to identify the core transferable microbiota (CTM) in UC patients responsive to FMT therapy and to define the therapeutic mechanism of these strains in pre-clinical models. Methods IBD disease activity scores were used to define a clinical response. Metagenomic sequencing of a donor, recipient, and 4-week post-FMT faecal samples was performed to define the CTM. Strain-level transferability was defined using the StrainFinder algorithm. To define the transferable immune-reactive microbiota (TIM), IgA-seq was performed on a donor, recipient, and 4-week post-FMT faecal samples. TIM strains were isolated from faecal samples and gnotobiotic mouse models were used to evaluate their impact on mucosal immunity and mouse models of colitis. Results Here, we defined a CTM associated with clinical response to FMT for UC. Strain-level tracking of the CTM confirmed that clinical response correlated with strain transferability. In addition, we defined a core TIM by IgA-seq that correlated with clinical response. In humanised mouse models, these TIM were found to induce IgA in a T-cell independent manner. Colonisation of germ-free mice with a core TIM strain of Odoribacter induced IL-10-dependent, RORgt+/Foxp3+ iTreg cells and reduced the severity of transfer T-cell colitis in mono-colonised RAG−/− mice. Conclusion Our data highlight an immune-reactive, core transferable microbiota in responders to FMT for UC. Using pre-clinical mouse models of colitis, we define the mechanistic impact of these TIM in shaping mucosal immunity and guiding the response to UC. This work provides a framework for the rational selection of TIM for microbial-therapy in IBD.

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