Meningococcal serogroup B vaccination series initiation in the United States: A real-world claims data analysis.

In the United States (US), meningococcal serogroup B (MenB) vaccination has been recommended for 16-23-year-olds (preferably 16-18 years) based on shared clinical decision-making since 2015. MenB vaccine coverage (≥1 dose) by age 17 years has been reported, but initiation at older ages and by insurance type is unknown. In this retrospective cohort study, MarketScan claims data were analyzed to assess MenB vaccine series initiation (i.e. receipt of a first dose) during 2017-2020 among US commercially insured and Medicaid-covered individuals aged 16-18 and 19-23 years. Kaplan-Meier curves were generated to estimate series initiation at various times from index (latest of 1/1/2017 or 16th/19th birthday, depending on the cohort). Multivariable analyses were conducted to identify factors associated with series initiation. Among 1,450,354 Commercial and 1,140,977 Medicaid 16-18-year-olds, MenB vaccine series initiation rates within 3 years of each person's first eligibility were estimated to be 33% and 20%, respectively; among 1,857,628 Commercial and 747,483 Medicaid 19-23-year-olds, 3% and 1%, respectively. Factors identified to be significantly associated with increased likelihood of initiating a MenB vaccine series included co-administration of meningococcal serogroups ACWY (MenACWY) vaccine, younger age, female sex, nonwhite race (Medicaid only), New England or Middle Atlantic location (Commercial only), urban residence, and previous influenza vaccination. MenB vaccine series initiation among the studied US adolescents and young adults was low. There is a need for continued efforts to better understand barriers to the uptake of vaccines that are recommended based on shared clinical decision-making.

Estimating the cost of university-based outbreaks of serogroup B meningococcal disease with different pre-matriculation vaccination policies in the United States.

Objective: We developed an Excel-based cost calculator to assess the economic burden of university-based Neisseria meningitidis serogroup B (MenB) outbreaks. Participants: Hypothetical university with 6,354 students. Methods: Total societal costs of outbreak were estimated for three MenB pre-matriculation immunization policies-vaccination required, vaccination recommended, and no vaccine policy-under three different cost assumptions (low/mid-range/high cost). Results: Mid-range cost estimates of an outbreak under "no policy" were $2.60 and $2.70 million (of which 35% were incurred by the university) if targeting all undergraduates for mass vaccination with a two-/three-dose vaccine, respectively. The "required" and "recommended" policies lowered the burden to $2.17-$2.18 million and $2.34-$2.39 million, respectively. For a larger university with 40,000 students, costs were almost $9 million for a two-dose vaccine with "no policy" in place. Conclusions: The economic burden of a university MenB outbreak is substantial, but could be mitigated by a pre-matriculation MenB vaccination requirement or recommendation.

Meningococcal Vaccination Rates Among People With a New Diagnosis of HIV Infection in the US.

Importance: In the United States, individuals with HIV infection have been recommended to receive a 2-dose series of the meningococcal A, C, W, Y (MenACWY) vaccine since 2016 owing to their increased risk of meningococcal disease. Objective: To examine uptake and time to receipt of the MenACWY vaccine among people with a new diagnosis of HIV. Design, Setting, and Participants: This cohort study used health insurance data from the US Optum Research Database from January 1, 2016, through March 31, 2018, to retrospectively identify 1208 individuals aged 2 years or older with 1 or more inpatient claim or 2 or more outpatient claims evidencing a new diagnosis of HIV infection and with continuous insurance enrollment for 12 or more months before and 6 or more months after diagnosis. Follow-up was 6 to 33 months. Statistical analysis was conducted from March 7, 2019, to January 5, 2022. Exposure: Receipt of the MenACWY vaccine. Main Outcomes and Measures: The coprimary outcomes were uptake and time to receipt of 1 or more doses of the MenACWY vaccine after a new HIV diagnosis. Secondary outcomes included uptake and time to receipt of 2 or more doses of the MenACWY vaccine. Vaccination uptake and receipt were estimated by Kaplan-Meier analysis; factors associated with receipt of 1 or more doses of the MenACWY vaccine were identified with multivariable Cox proportional hazards regression analysis. Results: Of 1208 individuals eligible for vaccination (1024 male patients [84.8%]; mean [SD] age, 38.8 [12.5] years; 35 [2.9%] Asian; 273 [22.6%] Black; 204 [16.9%] Hispanic; 442 [36.6%] White), 16.3% were estimated to have received a first dose of the MenACWY vaccine in the 2 years after a new HIV diagnosis. Among individuals who received a first dose, at 1 year or more of enrollment after the first dose, 66.2% were estimated to have received a second dose within 1 year of the first dose. Factors statistically significantly associated with uptake of the MenACWY vaccine included receipt of a pneumococcal vaccine (hazard ratio [HR], 23.03; 95% CI, 13.93-38.09), attendance at a well-care visit (HR, 3.67; 95% CI, 1.11-12.12), West or Midwest geographic region (West: HR, 2.24; 95% CI, 1.44-3.47; Midwest: HR, 1.78; 95% CI, 1.16-2.71), and male sex (HR, 2.72; 95% CI, 1.18-6.26), whereas age of 56 years or older was significantly associated with reduced uptake of the MenACWY vaccine (HR, 0.42; 95% CI, 0.18-0.97). Conclusions and Relevance: This cohort study suggests that MenACWY vaccine uptake among people with a new diagnosis of HIV was low, highlighting the need to educate patients and clinicians about the recommendations for conditions such as HIV infection that increase the risk of meningococcal disease among high-risk populations.

Real-world implementation of 4-component meningococcal serogroup B vaccine (4CMenB): implications for clinical practices.

INTRODUCTION: Invasive meningococcal disease due to serogroup B (MenB) is an uncommon but life-threatening disease. The 4-component meningococcal serogroup B vaccine (4CMenB) is the only MenB vaccine with real-world evidence supporting a reduction in incidence without safety concerns. AREAS COVERED: We reviewed recommendations and real-world implementation of 4CMenB in National Immunization Programs (NIPs) and implications for clinical practice through a non-systematic literature search. EXPERT OPINION: 4CMenB is registered in 45 countries, 33 of which recommend it clinically: nine for infants, children, adolescents, and high-risk groups; 11 for infants and high-risk groups; the US for individuals aged 16-23 years and high-risk groups; two for infants; 10 for high-risk groups and/or outbreak control. Dosing schedule varies between countries. To date, nine countries include 4CMenB in their NIP: UK, Andorra, Ireland, Italy, San Marino, Lithuania, Malta, Czech Republic, and Portugal. Australia funds it for Aboriginal and Torres Strait Islander children under 2 years, and high-risk individuals. South Australia funds for all infants and adolescents. Many factors influenced introduction into NIPs: disease burden, public awareness, cost-effectiveness, prior meningococcal vaccination programs, efficacy and safety profile. In the future, more countries might consider including 4CMenB in their NIP due to growing evidence on effectiveness and safety.

A Real-world Claims Data Analysis of Meningococcal Serogroup B Vaccine Series Completion and Potential Missed Opportunities in the United States.

BACKGROUND: In the United States, meningococcal serogroup B (MenB) vaccination is recommended for 16-23-year-olds based on shared clinical decision-making. We estimated series completion among individuals initiating MenB vaccination for the 2 available vaccines: MenB 4-component (MenB-4C, doses at 0 and ≥1 month) and MenB factor H binding protein (MenB-FHbp, doses at 0 and 6 months). METHODS: This retrospective health insurance claims data analysis included 16-23-year-olds who initiated MenB vaccination (index date) during January 2017 to November 2018 (MarketScan Commercial Claims and Encounters Database) or January 2017 to September 2018 (MarketScan Multi-State Medicaid Database) and had continuous enrollment for ≥6 months before and ≥15 months after index. The main outcome was MenB vaccine series completion within 15 months. Among noncompleters, preventive care/well-child and vaccine administrative office visits were identified as potential missed opportunities for series completion. Robust Poisson regression models identified independent predictors of series completion. RESULTS: In the Commercial (n = 156,080) and Medicaid (n = 57,082) populations, series completion was 56.7% and 44.7%, respectively, and was higher among those who initiated MenB-4C versus MenB-FHbp (61.1% versus 49.8% and 47.8% versus 33.9%, respectively; both P < 0.001). Among noncompleters, 40.2% and 34.7% of the Commercial and Medicaid populations, respectively, had ≥1 missed opportunity for series completion. Receipt of MenB-4C and younger age were independently associated with a higher probability of series completion. CONCLUSIONS: Series completion rates were suboptimal but were higher among those who initiated MenB-4C. To maximize the benefits of MenB vaccination, interventions to improve completion and reduce missed opportunities should be implemented.

Low Meningococcal Vaccination Rates Among Patients With Newly Diagnosed Complement Component Deficiencies in the United States.

Meningococcal vaccination is recommended for patients with complement component deficiencies (CDs) in the United States. In this retrospective database study, only 4.6% and 2.2% of patients received MenACWY and MenB vaccination, respectively, within 3 years of CD diagnosis. Thus, meningococcal vaccination rates among patients with CDs need to be improved.

National and State-Level Composite Completion of Recommended Vaccines Among Adolescents in the United States, 2015-2018.

BACKGROUND: Routine adolescent vaccination recommendations in the United States include tetanus, diphtheria, and acellular pertussis, quadrivalent meningococcal conjugate vaccine, and human papillomavirus vaccines. Although coverage for these individual vaccines is known, limited data are available on composite completion for all three vaccines. METHODS: This cross-sectional analysis of pooled 2015-2018 National Immunization Survey-Teen data used logistic regression to estimate model-adjusted composite vaccination completion nationally and by state among United States adolescents aged 17 years. National Immunization Survey-Teen data were combined with state-level data to estimate a multilevel model identifying factors associated with composite vaccination completion. RESULTS: The pooled model-adjusted composite vaccination completion was 30.6% (95% confidence interval [CI], 30.13%-31.04%) nationally, varying from 11.3% in Idaho (6.91%-17.95%) to 56.4% (49.81%-62.82%) in Rhode Island. Individual-level factors with the greatest impact on composite completion were having a provider's recommendation for human papillomavirus vaccination (odds ratio, 3.24; 95% CI, 2.76-3.80) and a check-up visit at age 16-17 years (odds ratio, 2.35; 95% CI, 1.80-3.07), with other individual-level factors associated with completion including being Medicaid insured, female, Hispanic, or non-Hispanic black. State-level quadrivalent meningococcal conjugate vaccination mandates were also associated with an increased likelihood of composite vaccination completion (odds ratio, 1.64; 95% CI, 1.16-2.33). CONCLUSIONS: Fewer than one-third of 17-year-old individuals have completed all three recommended vaccines, with rates varying by state. Although this study identified implementable strategies to improve composite completion, additional research is needed to further understand factors associated with adolescent vaccination completion.

Meningococcal B vaccination coverage among older adolescents in the United States.

BACKGROUND: Serogroup B meningococcal (MenB) vaccination recommendations for adolescents in the United States (US) include routine vaccination for all individuals at increased risk and vaccination for individuals not at increased risk aged 16-23 years (preferred age 16-18 years) based on shared clinical decision-making. The two licensed MenB vaccines require administration of ≥2 doses. METHODS: This cross-sectional study analyzed 2017-2018 National Immunization Survey-Teen (NIS-Teen) data to evaluate ≥1 dose and ≥2 dose MenB vaccination coverage among adolescents aged 17 years. Multivariable logistic regression was used to further evaluate determinants of MenB vaccination. RESULTS: Nationally, MenB vaccination coverage among 17-year-olds increased from 14.5% in 2017 to 17.2% in 2018 for ≥1 dose and from 6.3% to 8.4% for ≥2 doses. MenB vaccination coverage (2017-2018) was the lowest in the South (≥1 dose: 14.6%; ≥2 doses: 6.3%) and highest in the Northeast region (18.3% and 9.3%), with variation observed by census division. Adolescents were more likely to have received ≥1 dose of MenB vaccine if they had any Medicaid insurance (odds ratio [OR], 1.77; 95% confidence interval [CI], 1.32-2.39) or had received human papillomavirus (OR, 1.94; 95% CI, 1.41-2.67) or meningococcal A, C, W, and Y (OR, 4.03; 95% CI, 2.92-5.56) vaccinations. CONCLUSIONS: MenB first-dose coverage in the US is low, and even lower for a second dose, with regional variation. Being up to date with other routinely administered vaccines increased the likelihood of receiving MenB vaccination.

Meningococcal vaccination in patients with newly diagnosed asplenia in the United States.

BACKGROUND: Patients with asplenia are recommended to receive meningococcal ACWY (MenACWY) and B (MenB) vaccines in the United States (US). OBJECTIVES: To examine uptake and time to receipt of meningococcal vaccines in newly diagnosed asplenia patients, and identify factors associated with vaccination. METHODS: For this retrospective database analysis, patients were identified from 1/1/2010 (MenACWY) or 1/1/2015 (MenB) through 3/31/2018 from an administrative claims database including commercially insured US patients with ≥1 inpatient or ≥2 outpatient claims with evidence of a new asplenia diagnosis (sickle cell disease was excluded); continuous enrollment for ≥12 months before and ≥6 months after the index date; and age ≥2 (MenACWY) or ≥10 (MenB) years. Co-primary outcomes were uptake and time to receipt of ≥1 dose, separately for MenACWY and MenB, by Kaplan-Meier analysis. Cox proportional hazards regression models were used to identify characteristics associated with vaccination. RESULTS: Among 2,273 and 741 patients eligible for the MenACWY and MenB analyses, respectively, 28.1% and 9.7% received MenACWY and MenB in the first 3 years after a new asplenia diagnosis. Patients were more likely to receive meningococcal vaccines if they had received pneumococcal vaccines (MenACWY: hazard ratio [HR] 26.02; 95% confidence interval [CI] 21.01-32.22; MenB: HR 3.89; 95% CI 2.07-7.29) or attended ≥1 well-care visit (MenACWY: HR 6.63; 95% CI 4.84-9.09; MenB: HR 11.17; 95% CI 3.02-41.26). CONCLUSIONS: Meningococcal vaccination rates among newly diagnosed asplenia patients were low, highlighting the need to educate providers about the recommendations for high-risk conditions and ensure healthcare access for vulnerable patients.

Four-component Meningococcal Serogroup B Vaccine Induces Antibodies With Bactericidal Activity Against Diverse Outbreak Strains in Adolescents.

BACKGROUND: Neisseria meningitidis serogroup B (MenB) causes most meningitis outbreaks worldwide. We evaluated the ability of the 4-component MenB vaccine (4CMenB) to induce bactericidal activity against outbreak strains in adolescents. METHODS: Individual sera from 20 United States and 23 Chilean adolescents who received 2 doses of 4CMenB 2 months apart were assayed at prevaccination and 1 month after second dose using a human complement serum bactericidal antibody assay (hSBA) against a full or subset strain panel consisting of 14 MenB outbreak strains and 1 MenW hyperendemic strain collected between 2001 and 2017 in the United States, United Kingdom, and France. Bactericidal activity was determined as the percentage of adolescents with hSBA titer ≥1:4 or ≥1:8. RESULTS: One month after the second 4CMenB dose, antibodies from 65% to 100% of the US adolescents were able to kill 12 of 15 strains at 1:4 dilution. The remaining 3 strains were killed by 45%, 25%, and 15% of US adolescent sera. Similar percentages exhibited hSBA titers of ≥1:8. Across a subset of 4 strains, point estimates for the percentages of Chilean and US adolescents with hSBA titers of ≥1:4 after the second 4CMenB dose were similar (100% for strain M27703, 74% vs. 80% for M26312, 52% vs. 45% for M08 0240745), except for strain M39090 (91% vs. 65%). CONCLUSIONS: This study was the first to evaluate bactericidal activity elicited by a MenB vaccine against 15 outbreak strains. Two doses of 4CMenB elicited bactericidal activity against MenB outbreak strains and a hyperendemic MenW strain.

Determinants of Meningococcal ACWY vaccination in adolescents in the US: completion and compliance with the CDC recommendations.

Since 2011, the Advisory Committee on Immunization Practices (ACIP) guidelines for routine MenACWY vaccination in the US include a primary dose before age 16 y, preferably at ages 11-12 y, with a booster dose at age 16 y. Data on rates and drivers of meningococcal vaccination completion (receipt of both doses) and compliance with recommendations (receipt of primary dose at ages 11-12 y followed by booster at 16 y) down to state-level are limited.This study evaluated rates and determinants of MenACWY vaccination completion and compliance in adolescents aged 17 y based on data from the annual National Immunization Survey-Teen between 2011 and 2016. Individual- and state-level determinants of completion and compliance were assessed using uni-level and multi-level multivariable regression models. Average national rates were 23.2% and 12.1% for completion and compliance, respectively, with large inter-state variation observed (completion: 8.7-39.7%; compliance: 3.1-26.2%). Beyond the state of residence, factors significantly associated with a higher likelihood of both completion and compliance included being male, up-to-date on other routine vaccines, having private or hospital-based vaccine providers (vs. public) and having >1 child in the household. Factors specifically associated with completion included having >1 annual health-care visit and presence of a booster-dose vaccine mandate, while a history of asthma and high-risk health conditions had a positive association with compliance. State-level determinants of completion and compliance included pediatricians-to-children ratio and the proportion of Immunization Information System use among adolescents, respectively. Outcomes of this study may help guide clinical, policy and educational interventions to further increase MenACWY completion rates and reduce disparities in vaccination.

Meningococcal-group B (MenB) vaccine series completion and adherence to dosing schedule in the United States: A retrospective analysis by vaccine and payer type.

BACKGROUND: Two MenB vaccines with different dosing schedules are approved in the US: MenB-4C (2 doses) and MenB-FHbp (2-3 doses). Both vaccines were licensed on the basis of immunogenicity demonstrated after vaccine series completion. We evaluated vaccination completion and adherence to dosing schedules. METHODS: This retrospective analysis used data from MarketScan Commercial Claims and Encounters Database (Commercial) January 1, 2015 - February 28, 2018 and Multi-State Medicaid Database (Medicaid) January 1, 2015 - December 31, 2017 to examine vaccine series completion and adherence to dosing schedule in individuals who initiated a MenB series at ages 16-23 years. Vaccine series completion and dose schedule adherence were assessed during a 15-month follow-up period after the first dose. Completion was defined as individual receipt of the recommended number of doses, with current recommendations applied retroactively to allow individuals who initiated the MenB-FHbp series to be complete with either the 2- or the 3-dose schedule. RESULTS: The study population comprised 65,205 commercially-insured individuals (36,118 initiated MenB-4C; 29,087 initiated MenB-FHbp) and 13,535 Medicaid-covered individuals (10,153 initiated MenB-4C; 3382 initiated MenB-FHbp). In Commercial, 63% of individuals who initiated MenB-4C and 52% of individuals who initiated MenB-FHbp completed vaccination within 15 months; dosing schedule adherence was 62% for MenB-4C initiators and 18% for MenB-FHbp initiators. In Medicaid, 15-month completion rates for MenB-4C and MenB-FHbp initiators were 49% and 31%, respectively, with corresponding dosing schedule adherence of 48% and 8%. Among individuals who completed the series, median time to completion was 68 days for MenB-4C versus 258 days for MenB-FHbp in Commercial and 88 days for MenB-4C versus 309 days for MenB-FHbp in Medicaid. CONCLUSION: During the study period, MenB vaccine series completion was suboptimal. However, completion was significantly higher for MenB-4C, with notably shorter time to completion. This may reflect the flexible dosing schedule of MenB-4C.

Potential benefits of using a multicomponent vaccine for prevention of serogroup B meningococcal disease.

Meningococcal serogroup B (MenB) has become the main cause of invasive meningococcal disease in industrialized countries in recent years. The diversity of MenB strains and poor immunogenicity of the MenB capsular polysaccharide have made vaccine development challenging. Two MenB vaccines, including factor H binding protein (fHbp) as a major antigenic component, are now licensed for use. In addition to fHbp variant 1, the multicomponent vaccine 4CMenB contains neisserial heparin binding antigen, Neisseria adhesin A, and outer membrane vesicles containing porin A. The vast majority of circulating MenB strains contain genes encoding at least one 4CMenB component and many express genes for more than one vaccine antigen. Recent studies have suggested that serum bactericidal activity is enhanced against strains that express two or more vaccine antigens. Bacterial killing may also occur when antibodies to vaccine components are collectively present at levels that would individually be sub-lethal. The evaluation of immune responses to separate vaccine components does not take cooperative activity into account and may underestimate the overall protection. Available data on 4CMenB effectiveness indicate that this multicomponent vaccine affords broad coverage and protection against MenB disease. 4CMenB also has the potential to protect against disease caused by non-MenB meningococci and Neisseria gonorrhoeae.

Meningococcal Vaccination Among Adolescents in the United States: A Tale of Two Age Platforms.

PURPOSE: Despite recommended routine vaccination with meningococcal conjugate vaccine (MenACWY) at ages 11-12 years with a booster at age 16 years, national estimates indicate MenACWY uptake is lower in older adolescents than younger adolescents. This study aimed to identify factors associated with MenACWY uptake among adolescents. METHODS: Commercial Claims and Encounters (CCAE) and Medicaid MarketScan Databases from 2011 to 2016 were retrospectively analyzed (2017) to determine receipt of ≥1 dose of MenACWY during early (10.5 through 13 years) and late (15.5 through 18 years) adolescence. Multivariable logistic regression and nonlinear decomposition analyses were used to identify factors associated with MenACWY vaccination, potential missed opportunities, and differences between age groups. RESULTS: A larger proportion of younger adolescents than older adolescents received MenACWY: CCAE, 71.7% versus 48.9% (p < .001); Medicaid, 59.3% versus 31.8% (p < .001), respectively. In multivariable models (CCAE), older adolescents were less likely than younger ones to receive MenACWY (adjusted odds ratios [95% confidence intervals]: .68 [.67, .69]) and more likely to have a potential missed opportunity (1.27 [1.25, 1.28]). Decomposition results showed lower MenACWY uptake in older adolescents is largely attributed to fewer non-MenACWY vaccines received, fewer preventive care visits, and interaction with nonpediatric healthcare providers. DISCUSSION: Missed opportunities and infrequent preventive care encounters contribute to lack of vaccination in younger and older adolescents. However, the disparity in uptake between the two age groups was largely attributable to differences in healthcare utilization, suggesting a need for unique strategies to increase uptake among older adolescents, such as solidifying a vaccination platform for ages 16-18 years through encouragement of annual preventive care visits.

Optimizing the timing of 4CMenB vaccination in adolescents and young adults based on immune persistence and booster response data.

INTRODUCTION: Meningococcal disease has an incidence peak spread over several years during adolescence and young adulthood in the United States. Meningococcal serogroup B (MenB) vaccines have been introduced relatively recently and may help protect individuals in these age groups. Currently there is insufficient long-term experience to determine the duration of disease protection after any MenB vaccine. Understanding antibody persistence after primary vaccination and responses to booster can help inform MenB vaccination strategies and optimize disease prevention. Areas covered: Four studies in adolescents/young adults vaccinated with meningococcal B vaccine 4CMenB were reviewed with the aim to compare findings across studies and draw key learnings. The studies varied by geographic location, population characteristics, and timing of antibody measurement relative to primary vaccination. Expert opinion: Antibody persistence data for 4CMenB are substantial, extending 7.5 years post-primary vaccination. Vaccination at age 16-18 years may help protect adolescents throughout their highest age-based risk period. Similar robust responses to a single booster dose were observed 4 and 7.5 years after primary vaccination. In outbreak settings it is beneficial to have received prior vaccination; residual circulating antibodies may provide protection, and a single dose induces booster responses within 7 days, which is quicker than administration of a 2-dose series to vaccine-naïve individuals.

Intrinsic IL-21 signaling is critical for CD8 T cell survival and memory formation in response to vaccinia viral infection.

CD4 T cell help plays an important role in promoting CD8 T cell immunity to pathogens. In models of infection with vaccinia virus (VV) and Listeria monocytogenes, CD4 T cell help is critical for the survival of activated CD8 T cells during both the primary and memory recall responses. Still unclear, however, is how CD4 T cell help promotes CD8 T cell survival. In this study, we first showed that CD4 T cell help for the CD8 T cell response to VV infection was mediated by IL-21, a cytokine produced predominantly by activated CD4 T cells, and that direct action of IL-21 on CD8 T cells was critical for the VV-specific CD8 T cell response in vivo. We next demonstrated that this intrinsic IL-21 signaling was essential for the survival of activated CD8 T cells and the generation of long-lived memory cells. We further revealed that IL-21 promoted CD8 T cell survival in a mechanism dependent on activation of the STAT1 and STAT3 pathways and subsequent upregulation of the prosurvival molecules Bcl-2 and Bcl-x(L). These results identify a critical role for intrinsic IL-21 signaling in CD8 T cell responses to an acute viral infection in vivo and may help design effective vaccine strategies.

CD4 T cells are required for CD8 T cell survival during both primary and memory recall responses.

The role of CD4 T cell help in primary and secondary CD8 T cell responses to infectious pathogens remains incompletely defined. The primary CD8 T response to infections was initially thought to be largely independent of CD4 T cells, but it is not clear why some primary, pathogen-specific CD8 T cell responses are CD4 T cell dependent. Furthermore, although the generation of functional memory CD8 T cells is CD4 T cell help dependent, it remains controversial when the "help" is needed. In this study, we demonstrated that CD4 T cell help was not needed for the activation and effector differentiation of CD8 T cells during the primary response to vaccinia virus infection. However, the activated CD8 T cells showed poor survival without CD4 T cell help, leading to a reduction in clonal expansion and a diminished, but stable CD8 memory pool. In addition, we observed that CD4 T cell help provided during both the primary and secondary responses was required for the survival of memory CD8 T cells during recall expansion. Our study indicates that CD4 T cells play a crucial role in multiple stages of CD8 T cell response to vaccinia virus infection and may help to design effective vaccine strategies.