Early B cell transcriptomic markers of measles-specific humoral immunity following a 3rd dose of MMR vaccine.

B cell transcriptomic signatures hold promise for the early prediction of vaccine-induced humoral immunity and vaccine protective efficacy. We performed a longitudinal study in 232 healthy adult participants before/after a 3rd dose of MMR (MMR3) vaccine. We assessed baseline and early transcriptional patterns in purified B cells and their association with measles-specific humoral immunity after MMR vaccination using two analytical methods ("per gene" linear models and joint analysis). Our study identified distinct early transcriptional signatures/genes following MMR3 that were associated with measles-specific neutralizing antibody titer and/or binding antibody titer. The most significant genes included: the interleukin 20 receptor subunit beta/IL20RB gene (a subunit receptor for IL-24, a cytokine involved in the germinal center B cell maturation/response); the phorbol-12-myristate-13-acetate-induced protein 1/PMAIP1, the brain expressed X-linked 2/BEX2 gene and the B cell Fas apoptotic inhibitory molecule/FAIM, involved in the selection of high-affinity B cell clones and apoptosis/regulation of apoptosis; as well as IL16 (encoding the B lymphocyte-derived IL-16 ligand of CD4), involved in the crosstalk between B cells, dendritic cells and helper T cells. Significantly enriched pathways included B cell signaling, apoptosis/regulation of apoptosis, metabolic pathways, cell cycle-related pathways, and pathways associated with viral infections, among others. In conclusion, our study identified genes/pathways linked to antigen-induced B cell proliferation, differentiation, apoptosis, and clonal selection, that are associated with, and impact measles virus-specific humoral immunity after MMR vaccination.

Polygenic Prediction of Cellular Immune Responses to Mumps Vaccine.

In this report, we provide a follow-up analysis of a previously published genome-wide association study of host genetic variants associated with inter-individual variations in cellular immune responses to mumps vaccine. Here we report the results of a polygenic score (PGS) analysis showing how common variants can predict mumps vaccine response. We found higher PGS for IFNγ, IL-2, and TNFα were predictive of higher post-vaccine IFNγ (p-value = 2e-6), IL-2 (p = 2e-7), and TNFα (p = 0.004) levels, respectively. Control of immune responses after vaccination is complex and polygenic in nature. Our results suggest that the PGS-based approach enables better capture of the combined genetic effects that contribute to mumps vaccine-induced immunity, potentially offering a more comprehensive understanding than traditional single-variant GWAS. This approach will likely have broad utility in studying genetic control of immune responses to other vaccines and to infectious diseases.

Detection of SARS-CoV-2-Specific Cells Utilizing Whole Proteins and/or Peptides in Human PBMCs Using IFN-Æ´ ELISPOT Assay.

SARS-CoV-2 continues to threaten global public health, making COVID-19 immunity studies of utmost importance. Waning of antibody responses postinfection and/or vaccination and the emergence of immune escape variants have been ongoing challenges in mitigating SARS-CoV-2 morbidity and mortality. While a tremendous amount of work has been done to characterize humoral immune responses to SARS-CoV-2 virus and vaccines, cellular immunity, mediated by T cells, is critical for efficient viral control and protection and demonstrates high durability and cross-reactivity to coronavirus variants. Thus, ELISPOT, a standard assay for antigen-specific cellular immune response assessment, allows us to evaluate SARS-CoV-2-specific T-cell response by quantifying the frequency of SARS-CoV-2-specific cytokine-secreting cells in vitro. We have outlined a detailed procedure to study T-cell recall responses to SARS-CoV-2 in human peripheral blood mononuclear cells (PBMCs) following infection and/or vaccination using an optimized IFN-γ ELISPOT assay. Our methodologies can be adapted to assess other cytokines and are a useful tool for studying other viral pathogen and/or peptide-specific T-cell responses.

Frequencies of SARS-CoV-2 Spike Protein-Specific Memory B Cells in Human PBMCs, Quantified by ELISPOT Assay.

Vaccination against SARS-CoV-2 with coronavirus vaccines that elicit protective immune responses is critical to the prevention of severe disease and mortality associated with SARS-CoV-2 infection. Understanding the adaptive immune responses to SARS-CoV-2 infection and/or vaccination will continue to aid in the development of next-generation vaccines. Studies have shown the important role of SARS-CoV-2-specific antibodies for both disease resolution and prevention of COVID-19 serious sequelae following vaccination. However, antibody responses are short-lived, highlighting the importance of studying antigen-specific B-cell responses to better understand durable immunity and immunologic memory. Since the spike protein is the main target of antibody-producing B cells, we developed a SARS-CoV-2 memory B cell ELISPOT assay to measure the frequencies of spike-specific B cells after COVID-19 infection and/or vaccination. Here, we describe in detail the methodology for using this ELISPOT assay to quantify SARS-CoV-2 spike-specific memory B cells produced by infection and/or vaccination in human PBMC samples. Application of this assay may help better understand and predict SARS-CoV-2 recall immune responses and to develop potential B cell correlates of protection at the methodological level.

Restricted Omicron-specific cross-variant memory B-cell immunity after a 3rd dose/booster of monovalent Wuhan-Hu-1-containing COVID-19 mRNA vaccine.

The responsiveness/cross-binding of vaccine-induced memory B cells/MBCs to previous and emerging divergent SARS-CoV-2 variants (e.g., Omicron) is understudied. In this longitudinal study subjects receiving two or three doses of monovalent ancestral strain-containing COVID-19 mRNA vaccine were evaluated. In contrast to others, we observed significantly lower frequencies of MBCs reactive to the receptor-binding domain/RBD, the N-terminal domain/NTD, and the S1 of Omicron/BA.1, compared to Wuhan and Delta, even after a 3rd vaccine dose/booster. Our study is a proof of concept that MBC cross-reactivity to variants with greater sequence divergence from the vaccine strain may be overestimated and suggests that these variants may exhibit immune escape with reduced recognition by circulating pre-existing MBCs upon infection.

Vertical Transmission of SARS-CoV-2-Specific Antibodies and Cytokine Profiles in Pregnancy.

Despite intensive characterization of immune responses after COVID-19 infection and vaccination, research examining protective correlates of vertical transmission in pregnancy are limited. Herein, we profiled humoral and cellular characteristics in pregnant women infected or vaccinated at different trimesters and in their corresponding newborns. We noted a significant correlation between spike S1-specific IgG antibody and its RBD-ACE2 blocking activity (receptor-binding domain-human angiotensin-converting enzyme 2) in maternal and cord plasma (P < .001, R > 0.90). Blocking activity of spike S1-specific IgG was significantly higher in pregnant women infected during the third trimester than the first and second trimesters. Elevated levels of 28 cytokines/chemokines, mainly proinflammatory, were noted in maternal plasma with infection at delivery, while cord plasma with maternal infection 2 weeks before delivery exhibited the emergence of anti-inflammatory cytokines. Our data support vertical transmission of protective SARS-CoV-2-specific antibodies. This vertical antibody transmission and the presence of anti-inflammatory cytokines in cord blood may offset adverse outcomes of inflammation in exposed newborns.

A multifaceted approach for identification, validation, and immunogenicity of naturally processed and in silico-predicted highly conserved SARS-CoV-2 peptides.

SARS-CoV-2 remains a major global public health concern. Antibody waning and immune escape variant emergence necessitate the development of next generation vaccines that induce cross-reactive durable immune responses. T cell responses to SARS-CoV-2 demonstrate higher conservation, antigenic breadth, and longevity than antibody responses. Therefore, we sought to identify pathogen-derived T cell epitopes for a potential peptide-based vaccine. We pursued an approach leveraging: 1) liquid chromatography and tandem mass spectrometry (LC-MS/MS)-based identification of peptides from ancestral SARS-CoV-2-infected cell lines, 2) epitope prediction algorithms, and 3) overlapping peptide libraries. From this strategy, we identified 380 unique SARS-CoV-2-derived peptide sequences, including 53 antigenic HLA class I and class II peptides from multiple structural and non-structural/accessory viral proteins. These peptide sequences were highly conserved across variants of concern/interest (VoC/VoIs), and are estimated to achieve coverage of >96% of the world population. Our findings validate this discovery pipeline for peptide identification and immunogenicity testing, and are a crucial step toward the development of a next-generation multi-epitope SARS-CoV-2 peptide vaccine, and a novel vaccine platform methodology.

Associations of adaptive immune cell subsets with measles, mumps, and Rubella-Specific immune response outcomes.

The measles-mumps-rubella (MMR) vaccine has been widely used in the US, but measles and mumps outbreaks remain a public health issue in the US and elsewhere, even among individuals immunized with 2 doses of the vaccine. Immune correlates of vaccine-elicited protection against disease are typically assessed with serum antibody assays, but in some cases, these correlates fail to predict immunity, with the complexity and heterogeneity of the immune response. We used multicolor flow cytometry to evaluate changes in the frequency of peripheral T and B cell subsets in 82 study participants after receipt of a third dose of the M-M-RII vaccine (Merck & Co, Inc). We assessed correlations between flow cytometry variables and measles virus (MV), mumps virus (MuV), or rubella virus (RV)-specific immune response outcomes. Following a third vaccine dose, major changes were observed in the T-cell compartment. CD4+ T cell subsets were significantly increased from baseline to day 28, whereas CD8+ T cell subsets were predominantly decreased. Changes in regulatory T cells (Tregs) correlated with RV- and MV-specific immune outcomes and with high- and low-RV antibody responder groups, implicating the importance of Tregs in regulating MMR vaccine-induced immune responses. This information may help define additional correlates of protection and aid in the design of improved vaccines.

Excessive daytime sleepiness is associated with impaired antibody response to influenza vaccination in older male adults.

Background: The reduced effectiveness of standard-dose influenza vaccines in persons ≥65 years of age led to the preferential recommendation to use high-dose (HDFlu) or MF59-adjuvanted (MF59Flu) vaccines for this age group. Sleep is an important modulator of immune responses to vaccines and poor sleep health is common in older adults. However, potential effects of poor sleep health on immune responses to influenza vaccination in older adults remain largely unknown. Methods: We conducted a cohort study of 210 healthy participants age ≥65 years, who received either seasonal high-dose (HDFlu) or MF59-adjuvanted (MF59Flu) influenza vaccine. We assessed sleep characteristics in this cohort by standardized questionnaires and measured the antibody titer against influenza A/H3N2 virus in serum of study participants by hemagglutination inhibition assay on the day of immunization and 28 days thereafter. We then assessed the association between sleep characteristics and antibody titers. Results: Our results demonstrated that male, but not female, study participants with excessive daytime sleepiness had an impaired influenza A/H3N2-specific antibody response at Day 28 post-vaccination. No other associations were found between antibody titer and other sleep characteristics, including sleep quality and obstructive sleep apnea. Conclusion: Our results provide an additional and easily measured variable explaining poor vaccine effectiveness in older adults. Our results support that gaining sufficient sleep is a simple non-vaccine interventional approach to improve influenza immune responses in older adults. Our findings extend the literature on the negative influence of excessive daytime sleepiness on immune responses to influenza vaccination in older male adults.

Genome-wide determinants of cellular immune responses to mumps vaccine.

BACKGROUND: We have previously described genetic polymorphisms in candidate genes that are associated with inter-individual variations in antibody responses to mumps vaccination. To expand upon our previous work, we performed a genome-wide association study (GWAS) to discover host genetic variants associated with mumps vaccine-induced cellular immune responses. METHODS: We performed a GWAS of mumps-specific immune response outcomes (11 secreted cytokines/chemokines) in a cohort of 1,406 subjects. RESULTS: Among the 11 cytokine/chemokines we studied, four (IFN-γ, IL-2, IL-1ß, and TNFα) demonstrated GWAS signals reaching genome-wide significance (p < 5 × 10-8). A genomic region (encoding Sialic acid-binding immunoglobulin-type lectins/SIGLEC) located on chromosome 19q13 (p < 5 × 10-8) was associated with both IL-1ß and TNFα responses. The SIGLEC5/SIGLEC14 region contained 11 statistically significant single nucleotide polymorphisms (SNPs), including the intronic SIGLEC5 rs872629 (p = 1.3E-11) and rs1106476 (p = 1.32E-11) whose alternate alleles were significantly associated with decreased levels of mumps-specific IL-1ß (rs872629, p = 1.77E-09; rs1106476, p = 1.78E-09) and TNFα (rs872629, p = 1.3E-11; rs1106476, p = 1.32E-11) production. CONCLUSIONS: Our results suggest that SNPs in the SIGLEC5/SIGLEC14 genes play a role in cellular and inflammatory immune responses to mumps vaccination. These findings motivate further research into the functional roles of SIGLEC genes in the regulation of mumps vaccine-induced immunity.

Virus-specific and shared gene expression signatures in immune cells after vaccination in response to influenza and vaccinia stimulation.

Background: In the vaccine era, individuals receive multiple vaccines in their lifetime. Host gene expression in response to antigenic stimulation is usually virus-specific; however, identifying shared pathways of host response across a wide spectrum of vaccine pathogens can shed light on the molecular mechanisms/components which can be targeted for the development of broad/universal therapeutics and vaccines. Method: We isolated PBMCs, monocytes, B cells, and CD8+ T cells from the peripheral blood of healthy donors, who received both seasonal influenza vaccine (within <1 year) and smallpox vaccine (within 1 - 4 years). Each of the purified cell populations was stimulated with either influenza virus or vaccinia virus. Differentially expressed genes (DEGs) relative to unstimulated controls were identified for each in vitro viral infection, as well as for both viral infections (shared DEGs). Pathway enrichment analysis was performed to associate identified DEGs with KEGG/biological pathways. Results: We identified 2,906, 3,888, 681, and 446 DEGs in PBMCs, monocytes, B cells, and CD8+ T cells, respectively, in response to influenza stimulation. Meanwhile, 97, 120, 20, and 10 DEGs were identified as gene signatures in PBMCs, monocytes, B cells, and CD8+ T cells, respectively, upon vaccinia stimulation. The majority of DEGs identified in PBMCs were also found in monocytes after either viral stimulation. Of the virus-specific DEGs, 55, 63, and 9 DEGs occurred in common in PBMCs, monocytes, and B cells, respectively, while no DEGs were shared in infected CD8+ T cells after influenza and vaccinia. Gene set enrichment analysis demonstrated that these shared DEGs were over-represented in innate signaling pathways, including cytokine-cytokine receptor interaction, viral protein interaction with cytokine and cytokine receptor, Toll-like receptor signaling, RIG-I-like receptor signaling pathways, cytosolic DNA-sensing pathways, and natural killer cell mediated cytotoxicity. Conclusion: Our results provide insights into virus-host interactions in different immune cells, as well as host defense mechanisms against viral stimulation. Our data also highlights the role of monocytes as a major cell population driving gene expression in ex vivo PBMCs in response to viral stimulation. The immune response signaling pathways identified in this study may provide specific targets for the development of novel virus-specific therapeutics and improved vaccines for vaccinia and influenza. Although influenza and vaccinia viruses have been selected in this study as pathogen models, this approach could be applicable to other pathogens.

Genome-Wide Determinants of Cellular Immune Responses to Mumps Vaccine.

Background: We have previously described genetic polymorphisms in candidate genes that are associated with inter-individual variations in antibody responses to mumps vaccination. To expand upon our previous work, we performed a genome-wide association study (GWAS) to discover host genetic variants associated with mumps vaccine-induced cellular immune responses. Methods: We performed a GWAS of mumps-specific immune response outcomes (11 secreted cytokines/chemokines) in a cohort of 1,406 subjects. Results: Among the 11 cytokine/chemokines we studied, four (IFN-γ, IL-2, IL-1ß, and TNFα) demonstrated GWAS signals reaching genome-wide significance (p<5 x 10 -8 ). A genomic region (encoding Sialic acid-binding immunoglobulin-type lectins/SIGLEC) located on chromosome 19q13 (p<5×10 -8 ) was associated with both IL-1ß and TNFα responses. The SIGLEC5/SIGLEC14 region contained 11 statistically significant single nucleotide polymorphisms (SNPs), including the intronic SIGLEC5 rs872629 (p=1.3E-11) and rs1106476 (p=1.32E-11) whose alternate alleles were significantly associated with decreased levels of mumps-specific IL-1ß (rs872629, p=1.77E-09; rs1106476, p=1.78E-09) and TNFα (rs872629, p=1.3E-11; rs1106476, p=1.32E-11) production. Conclusions: Our results suggest that SNPs in the SIGLEC5/SIGLEC14 genes play a role in cellular and inflammatory immune responses to mumps vaccination. These findings motivate further research into the functional roles of SIGLEC genes in the regulation of mumps vaccine-induced immunity.

Functional humoral and cellular response of monovalent COVID-19-vaccines against Omicron BA.2 variant of SARS-CoV-2 in patients with chronic lymphocytic leukemia.

We designed a prospective study to evaluate the humoral (using a surrogate virus neutralization test) and cellular (using an IFN-γ ELISpot) immune response among patients with chronic lymphocytic leukemia (CLL) against Wuhan-Hu-1 and Omicron BA.2 strains of SARS-CoV-2, after mRNA-based vaccination. The proportion of patients with a functional humoral response was higher among untreated CLL patients compared to treated CLL patients against both Wuhan-Hu-1 and Omicron BA.2 after the second and the third dose of vaccination, and at 12 months after the first dose. The proportion of positive cellular response against the peptide pool covering the full-length Wuhan-Hu-1 spike protein was similar between untreated and treated CLL patients at all three timepoints. The cellular response to the mutated regions of BA.2 spike protein was lower than the response to the corresponding regions in the ancestral spike after the second dose, but this difference was eliminated after the third dose.

T Cell Transcriptional Signatures of Influenza A/H3N2 Antibody Response to High Dose Influenza and Adjuvanted Influenza Vaccine in Older Adults.

Older adults experience declining influenza vaccine-induced immunity and are at higher risk of influenza and its complications. For this reason, high dose (e.g., Fluzone) and adjuvanted (e.g., Fluad) vaccines are preferentially recommended for people age 65 years and older. However, T cell transcriptional activity shaping the humoral immune responses to Fluzone and Fluad vaccines in older adults is still poorly understood. We designed a study of 234 older adults (≥65 years old) who were randomly allocated to receive Fluzone or Fluad vaccine and provided blood samples at baseline and at Day 28 after immunization. We measured the humoral immune responses (hemagglutination inhibition/HAI antibody titer) to influenza A/H3N2 and performed mRNA-Seq transcriptional profiling in purified CD4+ T cells, in order to identify T cell signatures that might explain differences in humoral immune response by vaccine type. Given the large differences in formulation (higher antigen dose vs adjuvant), our hypothesis was that each vaccine elicited a distinct transcriptomic response after vaccination. Thus, the main focus of our study was to identify the differential gene expression influencing the antibody titer in the two vaccine groups. Our analyses identified three differentially expressed, functionally linked genes/proteins in CD4+ T cells: the calcium/calmodulin dependent serine/threonine kinase IV (CaMKIV); its regulator the TMEM38B/transmembrane protein 38B, involved in maintenance of intracellular Ca2+ release; and the transcriptional coactivator CBP/CREB binding protein, as regulators of transcriptional activity/function in CD4+ T cells that impact differences in immune response by vaccine type. Significantly enriched T cell-specific pathways/biological processes were also identified that point to the importance of genes/proteins involved in Th1/Th2 cell differentiation, IL-17 signaling, calcium signaling, Notch signaling, MAPK signaling, and regulation of TRP cation Ca2+ channels in humoral immunity after influenza vaccination. In summary, we identified the genes/proteins and pathways essential for cell activation and function in CD4+ T cells that are associated with differences in influenza vaccine-induced humoral immunity by vaccine type. These findings provide an additional mechanistic perspective for achieving protective immunity in older adults.

Longitudinal antibody titer, avidity, and neutralizing responses after SARS-CoV-2 infection.

While waning immunity and SARS-CoV-2 variant immune escape continue to result in high infection rates worldwide, associations between longitudinal quantitative, qualitative, and functional humoral immune responses after SARS-CoV-2 infection remain unclear. In this study, we found significant waning of antibody against Spike S1 (R = -0.32, p = 0.035) and N protein (R = -0.39, p = 0.008), while RBD antibody moderately decreased (R = -0.19, p = 0.203). Likewise, neutralizing antibody titer (ND50) waned over time (R = -0.46, p = 0.001). In contrast, antibody avidity increased significantly over time for Spike S1 (R = 0.62, p = 6.0e-06), RBD (R = 0.54, p = 2.0e-04), and N (R = 0.33, p = 0.025) antibodies. Across all humoral responses, ND50 strongly associated with Spike S1 (R = 0.85, p = 2.7e-13) and RBD (R = 0.78, p = 2.9e-10) antibodies. Our findings provide longitudinal insight into humoral immune responses after infection and imply the potential of Spike S1/RBD antibody titer as surrogate correlates of protection.

Seroprevalence of Measles Antibodies in a Highly MMR-Vaccinated Population.

As an extremely contagious pathogen, a high rate of vaccine coverage and the durability of vaccine-induced immunity are key factors to control and eliminate measles. Herein, we assessed the seroprevalence of antibodies specific to measles in a cohort of 1393 adults (20-44 years old). ELISA results showed a nontrivial proportion of 37.6% study subjects being negative for measles immunoglobulin G (IgG). We also found significant influences of sex and age of the study cohort on the IgG level. Our findings suggest that even within a highly vaccinated population, a subset of individuals may still have sub-optimal immunity against measles and potentially be susceptible during any future measles outbreaks.

Enhancing Immunogenicity of Influenza Vaccine in the Elderly through Intradermal Vaccination: A Literature Analysis.

BACKGROUND: Aging and immunosenescence lead to a gradual decline in immune responses in the elderly and the immunogenicity of influenza vaccines in this age group is sub-optimal. Several approaches have been explored to enhance the immunogenicity of influenza vaccines in the elderly, including incorporating vaccine adjuvant, increasing antigen dosage, and changing the route of vaccine administration. METHOD: We systematically compared the immunogenicity and safety of influenza vaccines administered by intradermal (ID) route and either intramuscular (IM) or subcutaneous (SC) routes in older adults aged ≥ 65. RESULTS: Of 17 studies included in this analysis, 3 studies compared the immunogenicity of ID vaccination to that of SC vaccination and 14 studies compared ID and IM vaccinations. ID vaccination was typically more immunogenic than both IM and SC routes at the same dosage. Importantly, a minimum of 3 µg of hemagglutinin antigen could be formulated in an ID influenza vaccine without a significant loss of immunogenicity. ID administration of standard-dose, unadjuvanted influenza vaccine was as immunogenic as IM injection of adjuvanted influenza vaccine. Waning of influenza-specific immunity was significant after 6 months, but there was no difference in waning immunity between vaccinations in ID, IM, or SC routes. While ID vaccination elicited local adverse reactions more frequently than other routes, these reactions were mild and lasted for no more than 3 days. CONCLUSIONS: We conclude that ID vaccination is superior to IM or SC routes and may be a suitable approach to compensate for the reduced immunogenicity observed in elderly adults. We also conclude that the main benefit of ID influenza vaccine lies in its dose-sparing effect. Additional research is still needed to further develop a more immunogenic ID influenza vaccine.

Rates of Asymptomatic COVID-19 Infection and Associated Factors in Olmsted County, Minnesota, in the Prevaccination Era.

Objective: To estimate rates and identify factors associated with asymptomatic COVID-19 in the population of Olmsted County during the prevaccination era. Patients and Methods: We screened first responders (n=191) and Olmsted County employees (n=564) for antibodies to SARS-CoV-2 from November 1, 2020 to February 28, 2021 to estimate seroprevalence and asymptomatic infection. Second, we retrieved all polymerase chain reaction (PCR)-confirmed COVID-19 diagnoses in Olmsted County from March 2020 through January 2021, abstracted symptom information, estimated rates of asymptomatic infection and examined related factors. Results: Twenty (10.5%; 95% CI, 6.9%-15.6%) first responders and 38 (6.7%; 95% CI, 5.0%-9.1%) county employees had positive antibodies; an additional 5 (2.6%) and 10 (1.8%) had prior positive PCR tests per self-report or medical record, but no antibodies detected. Of persons with symptom information, 4 of 20 (20%; 95% CI, 3.0%-37.0%) first responders and 10 of 39 (26%; 95% CI, 12.6%-40.0%) county employees were asymptomatic. Of 6020 positive PCR tests in Olmsted County with symptom information between March 1, 2020, and January 31, 2021, 6% (n=385; 95% CI, 5.8%-7.1%) were asymptomatic. Factors associated with asymptomatic disease included age (0-18 years [odds ratio {OR}, 2.3; 95% CI, 1.7-3.1] and >65 years [OR, 1.40; 95% CI, 1.0-2.0] compared with ages 19-44 years), body mass index (overweight [OR, 0.58; 95% CI, 0.44-0.77] or obese [OR, 0.48; 95% CI, 0.57-0.62] compared with normal or underweight) and tests after November 20, 2020 ([OR, 1.35; 95% CI, 1.13-1.71] compared with prior dates). Conclusion: Asymptomatic rates in Olmsted County before COVID-19 vaccine rollout ranged from 6% to 25%, and younger age, normal weight, and later tests dates were associated with asymptomatic infection.

Prevention of monkeypox with vaccines: a rapid review.

The largest outbreak of monkeypox in history began in May, 2022, and has rapidly spread across the globe ever since. The purpose of this Review is to briefly describe human immune responses to orthopoxviruses; provide an overview of the vaccines available to combat this outbreak; and discuss the various clinical data and animal studies evaluating protective immunity to monkeypox elicited by vaccinia virus-based smallpox vaccines, address ongoing concerns regarding the outbreak, and provide suggestions for the appropriate use of vaccines as an outbreak control measure. Data showing clinical effectiveness (~85%) of smallpox vaccines against monkeypox come from surveillance studies conducted in central Africa in the 1980s and later during outbreaks in the same area. These data are supported by a large number of animal studies (primarily in non-human primates) with live virus challenge by various inoculation routes. These studies uniformly showed a high degree of protection and immunity against monkeypox virus following vaccination with various smallpox vaccines. Smallpox vaccines represent an effective countermeasure that can be used to control monkeypox outbreaks. However, smallpox vaccines do cause side-effects and the replication-competent, second-generation vaccines have contraindications. Third-generation vaccines, although safer for use in immunocompromised populations, require two doses, which is an impediment to rapid outbreak response. Lessons learned from the COVID-19 pandemic should be used to inform our collective response to this monkeypox outbreak and to future outbreaks.