Mechanisms of innate and adaptive immunity to the Pfizer-BioNTech BNT162b2 vaccine.

Despite the success of the BNT162b2 mRNA vaccine, the immunological mechanisms that underlie its efficacy are poorly understood. Here we analyzed the innate and adaptive responses to BNT162b2 in mice, and show that immunization stimulated potent antibody and antigen-specific T cell responses, as well as strikingly enhanced innate responses after secondary immunization, which was concurrent with enhanced serum interferon (IFN)-γ levels 1 d following secondary immunization. Notably, we found that natural killer cells and CD8+ T cells in the draining lymph nodes are the major producers of this circulating IFN-γ. Analysis of knockout mice revealed that induction of antibody and T cell responses to BNT162b2 was not dependent on signaling via Toll-like receptors 2, 3, 4, 5 and 7 nor inflammasome activation, nor the necroptosis or pyroptosis cell death pathways. Rather, the CD8+ T cell response induced by BNT162b2 was dependent on type I interferon-dependent MDA5 signaling. These results provide insights into the molecular mechanisms by which the BNT162b2 vaccine stimulates immune responses.

Systems vaccinology of the BNT162b2 mRNA vaccine in humans.

The emergency use authorization of two mRNA vaccines in less than a year from the emergence of SARS-CoV-2 represents a landmark in vaccinology1,2. Yet, how mRNA vaccines stimulate the immune system to elicit protective immune responses is unknown. Here we used a systems vaccinology approach to comprehensively profile the innate and adaptive immune responses of 56 healthy volunteers who were vaccinated with the Pfizer-BioNTech mRNA vaccine (BNT162b2). Vaccination resulted in the robust production of neutralizing antibodies against the wild-type SARS-CoV-2 (derived from 2019-nCOV/USA_WA1/2020) and, to a lesser extent, the B.1.351 strain, as well as significant increases in antigen-specific polyfunctional CD4 and CD8 T cells after the second dose. Booster vaccination stimulated a notably enhanced innate immune response as compared to primary vaccination, evidenced by (1) a greater frequency of CD14+CD16+ inflammatory monocytes; (2) a higher concentration of plasma IFNγ; and (3) a transcriptional signature of innate antiviral immunity. Consistent with these observations, our single-cell transcriptomics analysis demonstrated an approximately 100-fold increase in the frequency of a myeloid cell cluster enriched in interferon-response transcription factors and reduced in AP-1 transcription factors, after secondary immunization. Finally, we identified distinct innate pathways associated with CD8 T cell and neutralizing antibody responses, and show that a monocyte-related signature correlates with the neutralizing antibody response against the B.1.351 variant. Collectively, these data provide insights into the immune responses induced by mRNA vaccination and demonstrate its capacity to prime the innate immune system to mount a more potent response after booster immunization.

Intratumor injected gold molecular clusters for NIR-II imaging and cancer therapy.

Surgical resections of solid tumors guided by visual inspection of tumor margins have been performed for over a century to treat cancer. Near-infrared (NIR) fluorescence labeling/imaging of tumor in the NIR-I (800 to 900 nm) range with systemically administrated fluorophore/tumor-targeting antibody conjugates have been introduced to improve tumor margin delineation, tumor removal accuracy, and patient survival. Here, we show Au25 molecular clusters functionalized with phosphorylcholine ligands (AuPC, ~2 nm in size) as a preclinical intratumorally injectable agent for NIR-II/SWIR (1,000 to 3,000 nm) fluorescence imaging-guided tumor resection. The AuPC clusters were found to be uniformly distributed in the 4T1 murine breast cancer tumor upon intratumor (i.t.) injection. The phosphocholine coating afforded highly stealth clusters, allowing a high percentage of AuPC to fill the tumor interstitial fluid space homogeneously. Intra-operative surgical navigation guided by imaging of the NIR-II fluorescence of AuPC allowed for complete and non-excessive tumor resection. The AuPC in tumors were also employed as a photothermal therapy (PTT) agent to uniformly heat up and eradicate tumors. Further, we performed in vivo NIR-IIb (1,500 to 1,700 nm) molecular imaging of the treated tumor using a quantum dot-Annexin V (QD-P3-Anx V) conjugate, revealing cancer cell apoptosis following PTT. The therapeutic functionalities of AuPC clusters combined with rapid renal excretion, high biocompatibility, and safety make them promising for clinical translation.

Circular RNA vaccine induces potent T cell responses.

Circular RNAs (circRNAs) are a class of RNAs commonly found across eukaryotes and viruses, characterized by their resistance to exonuclease-mediated degradation. Their superior stability compared to linear RNAs, combined with previous work showing that engineered circRNAs serve as efficient protein translation templates, make circRNA a promising candidate for RNA medicine. Here, we systematically examine the adjuvant activity, route of administration, and antigen-specific immunity of circRNA vaccination in mice. Potent circRNA adjuvant activity is associated with RNA uptake and activation of myeloid cells in the draining lymph nodes and transient cytokine release. Immunization of mice with engineered circRNA encoding a protein antigen delivered by a charge-altering releasable transporter induced innate activation of dendritic cells, robust antigen-specific CD8 T cell responses in lymph nodes and tissues, and strong antitumor efficacy as a therapeutic cancer vaccine. These results highlight the potential utility of circRNA vaccines for stimulating potent innate and T cell responses in tissues.

The immunology of SARS-CoV-2 infections and vaccines.

SARS-CoV-2, the virus that causes COVID-19, emerged in late 2019, and was declared a global pandemic on March 11th 2020. With over 50 million cases and 1.2 million deaths around the world, to date, this pandemic represents the gravest global health crisis of our times. Thus, the race to develop a COVID-19 vaccine is an urgent global imperative. At the time of writing, there are over 165 vaccine candidates being developed, with 33 in various stages of clinical testing. In this review, we discuss emerging insights about the human immune response to SARS-CoV-2, and their implications for vaccine design. We then review emerging knowledge of the immunogenicity of the numerous vaccine candidates that are currently being tested in the clinic and discuss the range of immune defense mechanisms that can be harnessed to develop novel vaccines that confer durable protection against SARS-CoV-2. Finally, we conclude with a discussion of the potential role of a systems vaccinology approach in accelerating the clinical testing of vaccines, to meet the urgent needs posed by the pandemic.

Examining the creation of synergy in community coalitions for smoke-free environments in Armenia and Georgia.

Community coalitions depend on their members to synergistically pool diverse resources, including knowledge and expertise, community connections and varied perspectives, to identify and implement strategies and make progress toward community health improvement. Several coalition theories suggest synergy is the key mechanism driving coalition effectiveness. The Community Coalition Action Theory (CCAT) asserts that synergy depends on how well coalitions engage their members and leverage their resources, which is influenced by coalition processes, member participation and satisfaction and benefits outweighing costs. The current study used mixed methods, including coalition member surveys (n = 83) and semi-structured interviews with leaders and members (n = 42), to examine the process of creating collaborative synergy in 14 community coalitions for smoke-free environments in Armenia and Georgia. Members, typically seven per coalition representing education, public health, health care and municipal administration sectors, spent an average of 16 hr/month on coalition-related work. Common benefits included making the community a better place to live and learning more about tobacco control. The greatest cost was attending meetings or events at inconvenient times. Members contributed various resources, including their connections and influence, skills and expertise and access to population groups and settings. Strong coalition processes, greater benefits and fewer costs of participation and satisfaction were correlated with leveraging of member resources, which in turn, was highly correlated with collaborative synergy. Consistent with CCAT, effective coalition processes created a positive climate where membership benefits outweighed costs, and members contributed their resources in a way that created collaborative synergy.

Smoke-free home restrictions in Armenia and Georgia: motives, barriers and secondhand smoke reduction behaviors.

BACKGROUND: Promoting smoke-free homes (SFHs) in Armenia and Georgia is timely given high smoking and secondhand smoke exposure (SHSe) rates and recent national smoke-free policy implementation. This study examined theoretical predictors (e.g. motives, barriers) of SFH status, and among those without SFHs, past 3-month SFH attempts and intent to establish SFHs in the next 3 months. METHODS: Multilevel logistic regression analyzed these outcomes using 2022 survey data from 1467 adults (31.6% past-month smokers) in Armenia (n = 762) and Georgia (n = 705). Correlates of interest included SHSe reduction behaviors and SFH motives and barriers; models controlled for country, community, age, sex, smoking status and other smokers in the home. RESULTS: In this sample, 53.6% had SFHs (Armenia: 39.2%; Georgia: 69.2%). Among those without SFHs, one-fourth had partial restrictions, no smokers in the home and/or recent SFH attempts; 35.5% intended to establish SFHs; and ∼70% of multiunit housing residents supported smoke-free buildings. We documented common SHSe reduction behaviors (opening windows, limiting smoking areas), SFH motives (prevent smell, protect children/nonsmokers) and barriers (smokers' resistance). Correlates of SFHs were being from Georgia, other smokers in the home, fewer SHSe reduction behaviors, greater motives and fewer barriers. Among participants without SFHs, correlates of recent SFH attempts were other smokers in the home, greater SHSe reduction behaviors and SFH motives, and fewer barriers; correlates of SFH intentions were being female, greater SHSe reduction behaviors, greater motives, and fewer barriers. CONCLUSIONS: SFH interventions should address motives, barriers and misperceptions regarding SHSe reduction behaviors. Moreover, smoke-free multiunit housing could have a great population impact.

Associations Between Pro/Anti-Tobacco Media and Messaging Exposure and Knowledge and Support of Smoke-Free Policy Among Adults in Armenia and Georgia.

CONTEXT: Despite high smoking rates, Armenia and Georgia recently adopted smoke-free policies (2022 and 2018). OBJECTIVE: We examined associations between exposure to pro-tobacco media (news opposing smoke-free policies; cigarette, e-cigarette, heated tobacco product [HTP] advertisements) and anti-tobacco media (media, community-based action) and (1) knowledge that the policies applied to alternative tobacco products (ATPs), and (2) support for the policies applying to ATPs and various settings. DESIGN: We analyzed 2022 survey data. SETTING: Data were from 28 communities in Armenia and Georgia. PARTICIPANTS: The sample comprised 1468 adults (31.6% past-month smokers). METHODS: We conducted multivariable regressions, controlling for country and sociodemographics. RESULTS: Participants were knowledgeable that the policy applied to ATPs (79.2%) and supportive of them applying to ATPs and various settings (means = 3.43 and 3.00; 1-4 = strongly support). Greater exposure to anti-tobacco media/community-based action correlated with more likely knowing that the policies applied to ATPs and greater support of the policies applying to various settings; HTP advertisement exposure correlated with less support of the policies applying to various settings. Less exposure to news opposing smoke-free policies and greater exposure to media supporting such policies correlated with greater support of the policies applying to ATPs. CONCLUSIONS: Media and community-based action may promote smoke-free policy knowledge and support. HTP advertisements may uniquely undermine smoke-free policies.

Examining smoke-free coalitions in Armenia and Georgia: baseline community capacity.

Local coalitions can advance public health initiative but have not been widely used or well-studied in low- and middle-income countries. This paper provides (i) an overview of an ongoing matched-pairs community-randomized controlled trial in 28 communities in Armenia and Georgia (N = 14/country) testing local coalitions to promote smoke-free policies/enforcement and (ii) characteristics of the communities involved. In July-August 2018, key informants (e.g. local public health center directors) were surveyed to compare their non-communicable disease (NCD) and tobacco-related activities across countries and across condition (intervention/control). More than half of the informants (50.0-57.1%) reported their communities had programs addressing hypertension, diabetes, cancer and human papilloma virus, with 85.7% involving community education and 32.1% patient education programs. Eleven communities (39.3%) addressed tobacco control, all of which were in Georgia. Of those, all included public/community education and the majority (72.7-81.8%) provided cessation counseling/classes, school/youth prevention programs, healthcare provider training or activities addressing smoke-free environments. Informants in Georgia versus Armenia perceived greater support for tobacco control from various sectors (e.g. government, community). No differences were found by condition assignment. This paper provides a foundation for presenting subsequent analyses of this ongoing trial. These analyses indicate wide variability regarding NCD-related activities and support across communities and countries.

Whole Genome Analysis and Assessment of the Metabolic Potential of Streptomyces carpaticus SCPM-O-B-9993, a Promising Phytostimulant and Antiviral Agent.

This work aimed to study the genome organization and the metabolic potential of Streptomyces carpaticus strain SCPM-O-B-9993, a promising plant-protecting and plant-stimulating strain isolated from brown semi-desert soils with very high salinity. The strain genome contains a linear chromosome 5,968,715 bp long and has no plasmids. The genome contains 5331 coding sequences among which 2139 (40.1%) are functionally annotated. Biosynthetic gene clusters (BGCs) of secondary metabolites exhibiting antimicrobial properties (ohmyungsamycin, pellasoren, naringenin, and ansamycin) were identified in the genome. The most efficient period of SCPM-O-B-9993 strain cultivation was 72 h: during this period, the culture went from the exponential to the stationary growth phase as well as exhibited excellent phytostimulatory properties and antiviral activity against the cucumber mosaic virus in tomatoes under laboratory conditions. The Streptomyces carpaticus SCPM-OB-9993 strain is a biotechnologically promising producer of secondary metabolites exhibiting antiviral and phytostimulatory properties.

Examining local smoke-free coalitions in Armenia and Georgia: context and outcomes of a matched-pairs community-randomised controlled trial.

INTRODUCTION: Local coalitions can advance public health initiatives such as smoke-free air but have not been widely used or well-studied in low-income and middle-income countries. METHODS: We conducted a matched-pairs community-randomised controlled trial in 28 communities in Armenia and Georgia (N=14/country) in which we helped establish local coalitions in 2019 and provided training and technical assistance for coalition activity promoting smoke-free policy development and enforcement (2019-2021). Surveys of ~1450 households (Fall 2018, May-June 2022) were conducted to evaluate coalition impact on smoke-free policy support, smoke-free home adoption, secondhand smoke exposure (SHSe), and coalition awareness and activity exposure, using multivariable mixed modelling. RESULTS: Bivariate analyses indicated that, at follow-up versus baseline, both conditions reported greater smoke-free home rates (53.6% vs 38.5%) and fewer days of SHSe on average (~11 vs ~12 days), and that intervention versus control condition communities reported greater coalition awareness (24.3% vs 12.2%) and activity exposure (71.2% vs 64.5%). Multivariable modelling indicated that intervention (vs control) communities reported greater rates of complete smoke-free homes (adjusted Odds Ratio [aOR] 1.55, 95% confiedence interval [CI] 1.11 to 2.18, p=0.011) and coalition awareness (aOR 2.89, 95% CI 1.44 to 8.05, p=0.043) at follow-up. However, there were no intervention effects on policy support, SHSe or community-based activity exposure. CONCLUSIONS: Findings must be considered alongside several sociopolitical factors during the study, including national smoke-free policies implementation (Georgia, 2018; Armenia, 2022), these countries' participation in an international tobacco legislation initiative, the COVID-19 pandemic and regional/local war). The intervention effect on smoke-free homes is critical, as smoke-free policy implementation provides opportunities to accelerate smoke-free home adoption via local coalitions. TRIAL REGISTRATION NUMBER: NCT03447912.

The inclusion of e-cigarettes and heated tobacco products in smoke-free home and car rules: A cross-sectional survey of adults in Armenia and Georgia.

INTRODUCTION: Understanding who includes e-cigarettes and heated tobacco products (HTPs) in smoke-free home or car rules could inform public health interventions, particularly in countries with high smoking prevalence and recently implemented national smoke-free laws, like Armenia and Georgia. METHODS: In 2022, we conducted a cross-sectional survey among 1468 adults in 28 Armenian and Georgian communities (mean age=42.92 years; 51.4% female, 31.6% past-month smoking). Multilevel regression (accounting for clustering within communities; adjusted for sociodemographics and cigarette use) examined e-cigarette/HTP perceptions (risk, social acceptability) and use intentions in relation to: 1) including e-cigarettes/HTPs in home and car rules among participants with home and car rules, respectively (logistic regressions); and 2) intention to include e-cigarettes/HTPs in home rules (linear regression, 1 = 'not at all' to 7 = 'extremely') among those without home rules. RESULTS: Overall, 72.9% (n=1070) had home rules, 86.5% of whom included e-cigarettes/HTPs; 33.9% (n=498) had car rules, 81.3% of whom included e-cigarettes/HTPs. Greater perceived e-cigarette/HTP risk was associated with including e-cigarettes/HTPs in home rules (AOR=1.28; 95% CI: 1.08-1.50) and car rules (AOR=1.46; 95% CI: 1.14-1.87) and next-year intentions to include e-cigarettes/HTPs in home rules (ß=0.38; 95% CI: 0.25-0.50). Lower e-cigarette/HTP use intentions were associated with including e-cigarettes/HTPs in home rules (AOR=0.75; 95% CI: 0.63-0.88). While perceived social acceptability was unassociated with the outcomes, other social influences were: having children and no other household smokers was associated with including e-cigarettes/HTPs in car rules, and having children was associated with intent to include e-cigarettes/HTPs in home rules. CONCLUSIONS: Interventions to address gaps in home and car rules might target e-cigarette/HTP risk perceptions.

AS03 adjuvant enhances the magnitude, persistence, and clonal breadth of memory B cell responses to a plant-based COVID-19 vaccine in humans.

Vaccine adjuvants increase the breadth of serum antibody responses, but whether this is due to the generation of antigen-specific B cell clones with distinct specificities or the maturation of memory B cell clones that produce broadly cross-reactive antibodies is unknown. Here, we longitudinally analyzed immune responses in healthy adults after two-dose vaccination with either a virus-like particle COVID-19 vaccine (CoVLP), CoVLP adjuvanted with AS03 (CoVLP+AS03), or a messenger RNA vaccination (mRNA-1273). CoVLP+AS03 enhanced the magnitude and durability of circulating antibodies and antigen-specific CD4+ T cell and memory B cell responses. Antigen-specific CD4+ T cells in the CoVLP+AS03 group at day 42 correlated with antigen-specific memory B cells at 6 months. CoVLP+AS03 induced memory B cell responses, which accumulated somatic hypermutations over 6 months, resulting in enhanced neutralization breadth of monoclonal antibodies. Furthermore, the fraction of broadly neutralizing antibodies encoded by memory B cells increased between day 42 and 6 months. These results indicate that AS03 enhances the antigenic breadth of B cell memory at the clonal level and induces progressive maturation of the B cell response.

Community coalitions for smoke-free environments in Armenia and Georgia: A mixed methods analysis of coalition formation, implementation and perceived effectiveness.

Effective models for aligning public health and civil society at the local level have the potential to impact various global health issues, including tobacco. Georgia and Armenia Teams for Healthy Environments and Research (GATHER) is a collaboration between Armenia, Georgia and U.S. researchers involving a community randomized trial testing the impact of community coalitions to promote smoke-free policy adoption and compliance in various settings. Community Coalition Action Theory (CCAT) was used to guide and describe coalition formation, implementation and effectiveness. Mixed methods were used to evaluate 14 municipality-based coalitions in Georgia and Armenia, including semi-structured interviews (n = 42) with coalition leaders and active members, coalition member surveys at two timepoints (n = 85 and n = 83), and review of action plans and progress reports. Results indicated successful creation of 14 multi-sectoral coalitions, most commonly representing education, public health, health care, and municipal administration. Half of the coalitions created at least one smoke-free policy in specific settings (e.g., factories, parks), and all 14 promoted compliance with existing policies through no-smoking signage and stickers. The majority also conducted awareness events in school, health care, and community settings, in addition to educating the public about COVID and the dangers of tobacco use. Consistent with CCAT, coalition processes (e.g., communication) were associated with member engagement and collaborative synergy which, in turn, correlated with perceived community impact, skills gained by coalition members, and interest in sustainability. Findings suggest that community coalitions can be formed in varied sociopolitical contexts and facilitate locally-driven, multi-sectoral collaborations to promote health. Despite major contextual challenges (e.g., national legislation, global pandemic, war), coalitions were resilient, nimble and remained active. Additionally, CCAT propositions appear to be generalizable, suggesting that coalition-building guidance may be relevant for local public health in at least some global contexts.

Phosphorylcholine-conjugated gold-molecular clusters improve signal for Lymph Node NIR-II fluorescence imaging in preclinical cancer models.

Sentinel lymph node imaging and biopsy is important to clinical assessment of cancer metastasis, and novel non-radioactive lymphographic tracers have been actively pursued over the years. Here, we develop gold molecular clusters (Au25) functionalized by phosphorylcholine (PC) ligands for NIR-II (1000-3000 nm) fluorescence imaging of draining lymph nodes in 4T1 murine breast cancer and CT26 colon cancer tumor mouse models. The Au-phosphorylcholine (Au-PC) probes exhibit 'super-stealth' behavior with little interactions with serum proteins, cells and tissues in vivo, which differs from the indocyanine green (ICG) dye. Subcutaneous injection of Au-PC allows lymph node mapping by NIR-II fluorescence imaging at an optimal time of ~ 0.5 - 1 hour postinjection followed by rapid renal clearance. Preclinical NIR-II fluorescence LN imaging with Au-PC affords high signal to background ratios and high safety and biocompatibility, promising for future clinical translation.

Tobacco-related risk perceptions, social influences and public smoke-free policies in relation to smoke-free home restrictions: findings from a baseline cross-sectional survey of Armenian and Georgian adults in a community randomised trial.

OBJECTIVES: Given high prevalence of smoking and secondhand smoke exposure in Armenia and Georgia and quicker implementation of tobacco legislation in Georgia versus Armenia, we examined correlates of having no/partial versus complete smoke-free home (SFH) restrictions across countries, particularly smoking characteristics, risk perceptions, social influences and public smoking restrictions. DESIGN: Cross-sectional survey study design. SETTING: 28 communities in Armenia and Georgia surveyed in 2018. PARTICIPANTS: 1456 adults ages 18-64 in Armenia (n=705) and Georgia (n=751). MEASUREMENTS: We used binary logistic regression to examine aforementioned correlates of no/partial versus complete SFH among non-smokers and smokers in Armenia and Georgia, respectively. RESULTS: Participants were an average age of 43.35, 60.5% women and 27.3% smokers. In Armenia, among non-smokers, having no/partial SFHs correlated with being men (OR=2.63, p=0.001) and having more friend smokers (OR=1.23, p=0.002); among smokers, having no/partial SFHs correlated with being unmarried (OR=10.00, p=0.001), lower quitting importance (OR=0.82, p=0.010) and less favourable smoking attitudes among friends/family/public (OR=0.48, p=0.034). In Georgia, among non-smokers, having no/partial SFHs correlated with older age (OR=1.04, p=0.002), being men (OR=5.56, p<0.001), lower SHS risk perception (OR=0.43, p<0.001), more friend smokers (OR=1.49, p=0.002) and fewer workplace (indoor) restrictions (OR=0.51, p=0.026); among smokers, having no/partial SFHs correlated with being men (OR=50.00, p<0.001), without children (OR=5.88, p<0.001), daily smoking (OR=4.30, p=0.050), lower quitting confidence (OR=0.81, p=0.004), more friend smokers (OR=1.62, p=0.038) and fewer community restrictions (OR=0.68, p=0.026). CONCLUSIONS: Private settings continue to lack smoking restrictions in Armenia and Georgia. Findings highlight the importance of social influences and comprehensive tobacco legislation, particularly smoke-free policies, in changing household smoking restrictions and behaviours. TRIAL REGISTRATION NUMBER: NCT03447912.

Adjuvanting a subunit SARS-CoV-2 vaccine with clinically relevant adjuvants induces durable protection in mice.

Adjuvants enhance the magnitude and the durability of the immune response to vaccines. However, there is a paucity of comparative studies on the nature of the immune responses stimulated by leading adjuvant candidates. In this study, we compared five clinically relevant adjuvants in mice-alum, AS03 (a squalene-based adjuvant supplemented with α-tocopherol), AS37 (a TLR7 ligand emulsified in alum), CpG1018 (a TLR9 ligand emulsified in alum), O/W 1849101 (a squalene-based adjuvant)-for their capacity to stimulate immune responses when combined with a subunit vaccine under clinical development. We found that all four of the adjuvant candidates surpassed alum with respect to their capacity to induce enhanced and durable antigen-specific antibody responses. The TLR-agonist-based adjuvants CpG1018 (TLR9) and AS37 (TLR7) induced Th1-skewed CD4+ T cell responses, while alum, O/W, and AS03 induced a balanced Th1/Th2 response. Consistent with this, adjuvants induced distinct patterns of early innate responses. Finally, vaccines adjuvanted with AS03, AS37, and CpG1018/alum-induced durable neutralizing-antibody responses and significant protection against the B.1.351 variant 7 months following immunization. These results, together with our recent results from an identical study in non-human primates (NHPs), provide a comparative benchmarking of five clinically relevant vaccine adjuvants for their capacity to stimulate immunity to a subunit vaccine, demonstrating the capacity of adjuvanted SARS-CoV-2 subunit vaccines to provide durable protection against the B.1.351 variant. Furthermore, these results reveal differences between the widely-used C57BL/6 mouse strain and NHP animal models, highlighting the importance of species selection for future vaccine and adjuvant studies.

Systems biological assessment of human immunity to BNT162b2 mRNA vaccination.

The emergency use authorization of two COVID-19 mRNA vaccines in less than a year since the emergence of SARS-CoV-2, represents a landmark in vaccinology1,2. Yet, how mRNA vaccines stimulate the immune system to elicit protective immune responses is unknown. Here we used a systems biological approach to comprehensively profile the innate and adaptive immune responses in 56 healthy volunteers vaccinated with the Pfizer-BioNTech mRNA vaccine. Vaccination resulted in robust production of neutralizing antibodies (nAbs) against the parent strain and the variant of concern, B.1.351, but no induction of autoantibodies, and significant increases in antigen-specific polyfunctional CD4 and CD8 T cells after the second dose. The innate response induced within the first 2 days of booster vaccination was profoundly increased, relative to the response at corresponding times after priming. Thus, there was a striking increase in the: (i) frequency of CD14+CD16+ inflammatory monocytes; (ii) concentration of IFN- y in the plasma, which correlated with enhanced pSTAT3 and pSTAT1 levels in monocytes and T cells; and (iii) transcriptional signatures of innate responses characteristic of antiviral vaccine responses against pandemic influenza, HIV and Ebola, within 2 days following booster vaccination compared to primary vaccination. Consistent with these observations, single-cell transcriptomics analysis of 242,479 leukocytes demonstrated a ~100-fold increase in the frequency of a myeloid cluster, enriched in a signature of interferon-response transcription factors (TFs) and reduced in AP-1 TFs, one day after secondary immunization, at day 21. Finally, we delineated distinct molecular pathways of innate activation that correlate with CD8 T cell and nAb responses and identified an early monocyte-related signature that was associated with the breadth of the nAb response against the B1.351 variant strain. Collectively, these data provide insights into the immune responses induced by mRNA vaccines and demonstrate their capacity to stimulate an enhanced innate response following booster immunization.

Smokers' and Nonsmokers' Receptivity to Smoke-Free Policies and Pro- and Anti-Policy Messaging in Armenia and Georgia.

Garnering support for smoke-free policies is critical for their successful adoption, particularly in countries with high smoking prevalence, such as Armenia and Georgia. In 2018, we surveyed 1456 residents (ages 18-64) of 28 cities in Armenia (n = 705) and Georgia (n = 751). We examined support for cigarette and electronic nicotine delivery systems (ENDS)/heated tobacco product (HTP) smoke-free policies in various locations and persuasiveness of pro- and anti-policy messaging. Participants were an average age of 43.35, 60.5% female, and 27.3% current smokers. Nonsmokers versus smokers indicated greater policy support for cigarette and ENDS/HTP and greater persuasiveness of pro-policy messaging. Armenians versus Georgians generally perceived pro- and anti-policy messaging more persuasive. In multilevel linear regression, sociodemographics (e.g., female) and tobacco use characteristics (e.g., smoking less frequently, higher quitting importance) correlated with more policy support. Greatest policy support was for healthcare, religious, government, and workplace settings; public transport; schools; and vehicles carrying children. Least policy support was for bar/restaurant outdoor areas. The most compelling pro-policy message focused on the right to clean air; the most compelling anti-policy message focused on using nonsmoking sections. Specific settings may present challenges for advancing smoke-free policies. Messaging focusing on individual rights to clean air and health may garner support.