Safety Observation Study on Haemophilus Influenza Type B Conjugate Vaccines Injected at Different Sites in Chinese Infants

In the present study, the safety of Hoemophilus influenza type b conjugate vaccines inoculated in the upper arm deltoid and vastus lateralis muscle was evaluated. 680 infants aged 2-5 months and 6-12 months were selected to be the research subjects in whom the Hib conjugate vaccines were inoculated by injection in the upper arm deltoid and vastus lateralis muscle, respectively. The safety analysis indicated that there were no statistic differences in the incidence rates of adverse reactions when the Hib conjugate vaccines were inoculated at different sites. So we concluded that the safety of inoculation injection of Hib conjugate vaccines in vastus lateralis muscle was the same as that inoculated in the upper arm deltoid.

Adherence to Advisory Committee on Immunization Practices in diabetes mellitus patients in Saudi Arabia:A multicenter retrospective study

BACKGROUND Patients with diabetes mellitus(DM)are predisposed to an increased risk of infection signifying the importance of vaccination to protect against its potentially severe complications.The Centers for Disease Control and Prevention/Advisory Committee on Immunization Practices(CDC/ACIP)issued immunization recommendations to protect this patient population.AIM To assess the adherence of patients with DM to the CDC/ACIP immunization recommendations in Saudi Arabia and to identify the factors associated with the vaccine adherence rate.METHODS An observational retrospective study conducted in 2023 was used to collect data on the vaccination records from 13 diabetes care centers in Saudi Arabia with 1000 eligible patients in phase I with data collected through chart review and 709 patients in phase II through online survey.RESULTS Among participants,10.01%(n=71)had never received any vaccine,while 85.89%(n=609)received at least one dose of the coronavirus disease 2019(COVID-19)vaccine,and 34.83%(n=247)had received the annual influenza vaccine.Only 2.96%(n=21),2.11%(n=15),and 1.12%(n=8)received herpes zoster,tetanus,diphtheria,and pertussis(Tdap),and human papillomavirus(HPV)vaccines,respectively.For patients with DM in Saudi Arabia,the rate of vaccination for annual influenza and COVID-19 vaccines was higher compared to other vaccinations such as herpes zoster,Tdap,pneumococcal,and HPV.Factors such as vaccine recommendations provided by family physicians or specialists,site of care,income level,DM-related hospitalization history,residency site,hemoglobin A1c(HbA1c)level,and health sector type can significantly influence the vaccination rate in patients with DM.Among non-vaccinated patients with DM,the most reported barriers were lack of knowledge and fear of side effects.This signifies the need for large-scale research in this area to identify additional factors that might facilitate adherence to CDC/ACIP vaccine recommendations in patients with DM.CONCLUSION In Saudi Arabia,patients with DM showed higher vaccination rates for annual influenza and COVID-19 vaccines compared to other vaccinations such as herpes zoster,Tdap,pneumococcal,and HPV.Factors such as vaccine recommendations provided by family physicians or specialists,the site of care,income level,DM-related hospitalization history,residency site,HbA1c level,and health sector type can significantly influence the vaccination rate in patients with DM.

Immunogenicity and Efficacy of Liposome-encapsulated Influenza Split Vaccine in BALB/c Mice

The cellular immunity of current influenza split vaccine is relatively low. It is necessary to develop a novel vaccine to improve the cellular immunity. The authors of this study prepared liposome-encapsulated influenza split vaccine and tested it in BALB/c mice. The mice were immunized once with 4 μg of haemagglutinin of monovalent A/ New Caledonia/20/99 （H1N1 ） encapsulated with liposomes or the split virus vaccine only through intrastomach injection. In a comparative study, it was observed that the liposome-encapsulated vaccine elicited a higher neutralizing antibedy response, more effectively stimulated spleen cell proliferation, increased cell subsets like CD^4＋ and CD^4＋/ CD8^＋ , and triggered IL-4 and IFN-γ production.

Prevaccination Antibody Confers Additional Immune Responses to Repeated Yearly Influenza Vaccination in an Elderly Population

Annual vaccination is necessary to maintain humoral immunity in the elderly population. However, the factors influencing the response to influenza vaccination have not been completely identified. The aim of this study was to explore the factors that influenced antibody responses to repeated vaccination using measures that were both objective and quantitative. A total of 111 volunteers aged > 61 years were vaccinated subcutaneously with one dose of influenza vaccine from the 2005-2006 season through the 2009-2010 season. The factors that influenced antibody responses after vaccination were evaluated. The seroprotection rates (PRs) were significantly higher in responders (subjects with a higher antibody titer in the 2005-2006 season) than in nonresponders only in the 2006-2007 and 2007-2008 seasons. PRs after vaccination were significantly higher in seropositive individuals (subjects with a higher prevaccination antibody titer in the 2006-2007 season) than in seronegative individuals for all three virus strains in almost all of the 5 years. Age, gender, and vaccination in the 2004-2005 season did not influence the response. These results suggest that an immune response at a certain time point would predict immune responses only in the near future. However, prevaccination antibody titer in the following season is the ideal predictor for future responses that last over several influenza seasons.

Immunological Effect of Subunit Influenza Vaccine Entrapped by Liposomes

Objective To elevate the immunological effect of subunit influenza vaccine in infants and aged people （over 60） using liposomal adjuvant in the context of its relatively low immunity and to investigate the relation between vaccine antigens and liposomal characteristics. Methods Several formulations of liposomal subunit influenza vaccine were prepared. Their relevant characteristics were investigated to optimize the preparation method. Antisera obtained from immunizinged mice were used to evaluate the antibody titers of various samples by HI and EL1SA. Results Liposomal trivalent influenza vaccine prepared by film evaporation in combinedation with freeze-drying significantly increased its immunological effect in SPF Balb/e mice. Liposomal vaccine stimulated the antibody titer of H3N2, H1N1, and B much stronger than conventional influenza vaccine. As a result, liposomal vaccine （mean size： 4.5-5.5 pm, entrapment efficiency： 30%-40%） significantly increased the immunological effect of subunit influenza vaccine. Conclusion The immune effect of liposomal vaccine depends on different antigens, and enhanced immunity is not positively correlated with the mean size of liposome or its entrapped efficiency.

Wells’syndrome possibly caused by hematologic malignancy,influenza vaccination or ibrutinib:A case report

BACKGROUND Wells’ syndrome(eosinophilic cellulitis) is an uncommon eosinophilic dermatosis of uncertain pathogenesis,characterized by clinical polymorphism and suggestive but nonspecific histopathologic traits.Its course is recurrent,and response to therapy is unpredictable.In a case in which the patient has a number of potential triggers for the manifestation of Wells’ syndrome skin rash,the treating physician must decide or must make an assumption in order to establish the most likely clinical scenario.This is important for the patient’s future treatment plans.CASE SUMMARY We describe the clinical case of a 46-year-old female with chronic lymphocytic leukemia who had already received treatment for several months with ibrutinib.She was diagnosed with Wells’ syndrome 10 d after an influenza vaccination containing thimerosal.Based on the literature,the patient was treated with a course of oral steroids.Resolution of clinical symptoms and rash were observed in response to the treatment.Ibrutinib was not discontinued.CONCLUSION The etiology of Wells’ syndrome remains unknown.Clinically,it resembles bacterial cellulitis.Lack of response to antibiotic treatment should lead the physician to consider a diagnosis of Wells’ syndrome.Treating the underlying condition is important and may lead to resolution of the syndrome.However,the most common and effective treatment to limit the course of the disease are systemic steroids.

Antibody Dynamic Changes in SPF Chickens and SPF Ducks Immuned with Recombinant Avian Influenza Virus H5 Subtype Bivalent Inactivated Vaccine

To study the immune effect of recombinant avian influenza virus H5 subtype bivalent inactivated vaccine （ HSN1, Re-6 strain ＋ Re-4 strain） and to provide the basis for formulating reasonable immune procedure of avian influenza vaccine in clinical practice. A total of 12 batches of vaccines from three companies were used for the iannune of SPF chickens and SPF ducks. Each chicken or duck serum was separately collected every 3 weeks until the immunization up to the 24^th week. The serum antibody titers of Re-6 and Re-4 were detected. The results showed that the HI titers of the inoculated SPF chickens and SPF ducks roached the peak when the immune time were the 6^th and 3^rd week after the first immunization respectively; then the titer decreased gradually as time prolonged; the highest titer of SPF chickens was greater than that of SPF ducks; the high titer duration of SPF chickens were longer than that of SPF ducks ; and all the vaccines from the three companies showed a good immune effect.

Prevalence of influenza vaccination coverage amongst the first and third generation Asian adults in California, United States of America

The Asian population comprises the third largest ethnic minority in the state of California.However,influenza vaccination coverage amongst the overall Asian population,and the first and third-generation Asian’s have not been widely studied.Previous literature exploring generational status as a corelate of influenza immunization amongst Mexican identified Latino adults confirms disparities in influenza vaccination coverage by generation.This study aims to report on the prevalence of influenza vaccination coverage amongst the overall,first and third-generation Asians in California,and examine the correlates of influenza vaccination coverage in the aforementioned population.Methods:Cross-sectional data from the California Health Interview Survey 2016 for Asian adults was analyzed using IBM SPSS 25.0 for Mac.Descriptive statistics were utilized for reporting the frequencies and percentages of the selected variables.Weighted multivariable binary logistic regression was used to obtain adjusted odds ratios(95%confidence interval)and determine independent association between socioeconomic determinants and influenza vaccination coverage amongst the first and third-generation Asians at P<0.05.The analysis was adjusted for“visit to the doctor”and“insurance status”.Results:Thirteen point one percent(n=2,761)of the survey respondents(N=21,055)identified as Asians.The first-generation(n=1,857,67%)comprised the highest proportion of the Asian ethnic group.Influenza vaccination coverage was reported as 61.2%amongst the overall,61.1%amongst the first-generation and 70.9%amongst the third-generation respectively.All predictor variables were significant amongst the first-generation,however amongst the third-generation all variables except for location and living in a household of 3 and more,were significant predictors of influenza vaccination coverage.Conclusion:Compared to the other ethnic groups in California,the Asian respondents reported a higher percentage of influenza vaccination coverage.Influenza vaccination coverage was the highest amongst the third-generation Asians.Increased influenza vaccination coverage amongst the Asian ethnic group can be ascribed to higher educational attainment,a higher proportion choosing to visit a doctor as well as increased insurance coverage.

Analysis of 472,688 Severe Cases of COVID-19 in Brazil Showed Lower Mortality in Those Vaccinated against Influenza

Objective: To analyze the severe cases of COVID-19 in Brazil in 2020 and compare those vaccinated and unvaccinated against influenza in invasive ventilation, admission in Intensive Care Unit (ICU) and deaths. Method: Cross-sectional study with public data from the OpenDataSUS platform, regarding confirmed severe cases for COVID-19 in Brazil in the year 2020. Data were analyzed by SPSS, from the chi-square test of independence and binary logistic regression. Results: The population was 472,688 cases and 177,640 deaths, with a lethality of 37.58% in severe cases. The test of independence was highly significant in vaccinated survivors (<0.0001), and regression showed an almost twofold odds ratio for invasive ventilation, ICU admission, and death in unvaccinated cases. Conclusion: We recommend mass influenza vaccination as an adjuvant in combating the COVID-19 pandemic in Brazil.

Effect of Aluminum Hydroxide Adjuvant on the Immunogenicity of the 2009 Pandemic Influenza A/H1N1 Vaccine:Multi-level Modeling of Data with Repeated Measures

Objective To evaluate the effect of the aluminum hydroxide （Al-OH） adjuvant on the 2009 pandemic influenza A/H1N1 （pH1N1） vaccine. Methods In a multicenter, double-blind, randomized, placebo-controlled trial, participants received two doses of split-virion formulation containing 15 ug hemagglutinin antigen, with or without aluminum hydroxide （N-OH）. We classified the participants into six age categories （〉61 years, 41-60 years, 19-40 years, 13-18 years, 8-12 years, and 3-7 years） and obtained four blood samples from each participant on days 0, 21, 35, and 42 following the first dose of immunization. We assessed vaccine immunogenicity by measuring the geometric mean titer （GMT） of hemagglutination inhibiting antibody. We used a two-level model to evaluate the fixed effect of aluminum Al-OH and other factors, accounting for repeated measures. Results The predictions of repeated measurement on GMTs of formulations with or without Al-OH, were 80.35 and 112.72, respectively. Al-OH significantly reduced immunogenicity after controlling for time post immunization, age-group and gender. Conclusion The Al-OH adjuvant does not increase but actually reduces the immunogenicity of the split-virion pH1N1 vaccine.

Adjuvanted vaccines against influenza in the elderly

Influenza is an important public health issue, especially with the aging of the population, since the most serious consequences of the illness affect the elderly. Between 1979 and 2001, approximately 41000 annual deaths have been attributed to influenza in the United States （Dushoff, 2005）. Annual vaccination is a key strategy employed to combat this illness, and while it is very effective in healthy young adults, it is much less successful in the elderly. The impaired immune system with aging may contribute to this diminished ability of the vaccine to afford protection. Strategies to improve vaccine efficacy, particularly for the aged population, are necessary. One potential strategy is the inclusion of adjuvants in the vaccine formulations to enhance the immune response. Adjuvants have been shown to improve antibody production, allow dose-sparing, and potentially increase cross-reactivity. These benefits are important in combating both seasonal influenza and pandemic influenza, as current seasonal vaccine effectiveness depends on close matching to the circulating virus, and fast production of pandemic vaccines are key to their effectiveness. While much is still unknown about adjuvants, especially their mechanisms of action, their potential at improving the efficacy of influenza vaccines has been well recognized, particularly in the elderly.

Universal influenza virus vaccines： what can we learn from the human immune response following exposure to H7 subtype viruses？

Several universal influenza virus vaccine candidates based on eliciting antibodies against the hemagglutinin stalk domain are in development. Typically, these vaccines induce responses that target group 1 or group 2 hemagglutinins with Httle to no cross-group reactivity and protection. Similarly, the majority of human anti-stalk monoclonal antibodies that have been isolated are directed against group 1 or group 2 hemagglutinins with very few that bind to hemagglutinins of both groups. Here we review what is known about the human humoral immune response to vaccination and infection with H7 subtype influenza viruses on a polyclonal and monoclonal level. It seems that unlike vaccination with H5 hemagglutinin, which induces antibody responses mostly restricted to the group 1 stalk domain, H7 exposure induces both group 2 and cross-group antibody responses. A better understanding of this phenomenon and the underlying mechanisms might help to develop future universal influenza virus vaccine candidates.

Bioengineered pseudovirus nanoparticles displaying the HA1 antigens of influenza viruses for enhanced immunogenicity

Even with implementation of current influenza vaccines,influenza still claims up to 500,000 lives worldwide annually,indicating a need for a better vaccine strategy.We have developed a technology to generate unique S_(60)-HA1 pseudovirus nanoparticles(PVNPs)that display the receptor-binding HA1 domains of influenza viruses.Each self-assembled S_(60)-HA1 PVNP consists of a T=1 icosahedral S_(60) nanoparticle that resembles the inner shell of norovirus capsid and 60 surface-displayed HA1 antigens that are excellent vaccine targets.Soluble S_(60)-HA1 PVNPs presenting HA1 antigens of H7N9 influenza virus subtypes have been produced efficiently in large amount.Their three-dimensional(3D)structures have been solved by cryogenic electron microscopy.The PVNP-displayed HA1 antigens react with HA-specific antibody,and retain authentic sialic acid binding specificity and hemagglutinate human erythrocytes.The PVNPs are highly immunogenic,eliciting high titers of HA1-specific antibodies in mice and the mouse sera strongly inhibited hemagglutinations of homologous and heterologous influenza virus HA proteins.Therefore,the S_(60)-HA1 PVNPs may provide useful reagents to study influenza viruses and offer a potential new vaccine tactic to fight the deadly influenza disease.

Association between influenza vaccination and SARS-CoV-2 infection and its outcomes: systematic review and meta-analysis

Background:World Health Organization recommends that influenza vaccines should benefit as much of the population as possible,especially where resources are limited.Corona virus disease 2019(COVID-19)has become one of the greatest threats to health systems worldwide.The present study aimed to extend the evidence of the association between influenza vaccination and COVID-19 to promote the former.Methods:In this systematic review,four electronic databases,including the Cochrane Library,PubMed,Embase,and Web of Science,were searched for related studies published up to May 2022.All odds ratios(ORs)with 95%confidence intervals(CIs)were pooled by meta-analysis.Results:A total of 36 studies,encompassing 55,996,841 subjects,were included in this study.The meta-analysis for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection provided an OR of 0.80(95%CI:0.73–0.87).The statistically significant estimates for clinical outcomes were 0.83(95%CI:0.72–0.96)for intensive care unit admission,0.69(95%CI:0.57–0.84)for ventilator support,and 0.69(95%CI:0.52–0.93)for fatal infection,while no effect seen in hospitalization with an OR of 0.87(95%CI:0.68–1.10).Conclusion:Influenza vaccination helps limit SARS-CoV-2 infection and severe outcomes,but further studies are needed.Registration:PROSPERO,CRD42022333747.

Apoferritin nanoparticle based dual-antigen influenza conjugate vaccine with potential cross-protective efficacy against heterosubtypic influenza virus

Ferritin nanoparticles with self-assembling properties have been widely explored as vaccine carrier by displaying foreign antigens through genetic fusion strategy.In the present work,an apoferritin(AFt)nanoparticle was tested as influenza vaccine carrier by chemically conjugating a matrix protein 2 ectodomain(M2e)antigen peptide or/and the full-length hemagglutinin(HA)antigen on the outer surface of the AFt,with heterobifunctional sSMCC or SM(PEG)_(24) containing PEG chain as linkers.To each AFt nanoparticle,about 30-32 M2e or 1.8 HA antigen could be coupled.The AFt-(PEG)24-M2e,in which the M2e was coupled through SM(PEG)_(24) containing PEG chain,conferred higher protective efficacy in immunized mice than AFt-M2e did,but was less effective than AFt-(PEG)_(24)-HA.When both M2e and HA were coupled,the synthesized dual-antigen vaccine candidate AFt-(PEG)_(24)-M2e/HA elicited high level of M2e and HA antigen-specific antibodies and conferred 100%protection against lethal infection of homologous PR8 HI N1 virus strain and 70%protection against a heterologous A/FM/1/47(FM1,H1N1)strain,which was more effective than the M2e or HA single antigen vaccine candidates.The potential cross-protective effect of the dual-antigen vaccine was further demonstrated by significant specific hemagglutination inhibition(HAI)titers in serum of the immunized mice against three other heterologous viral strains including A/Singapore/GPl908/2015(IVR-180)H1N1,A/Anhui/1/2005 H5N1,and A/Hong Kong H3N2.

The effect of adjuvants on vaccine-induced antibody response against influenza in aged mice

While influenza remains a major threat to public health, researchers continue to search for a universal solution to improving the efficacy of the influenza vaccine. Even though influenza affects people of all different ages, it can be extremely hazardous to people of 65 years of age or older since that is the population that makes up the high majority of the death toll caused by influenza-related diseases. Elderly individuals suffer the effects of immunosenescence as they age, which is the diminishing of the overall immune response. Immunosenescence occurs by specifically affecting the adaptive immune response which controls the establishment of immunity after vaccination or infection. There are many studies under way that are trying to find a resolution to the problem of the influenza vaccine not providing enough protection in the elderly population. One of the possible strategies is to seek the use of an optimal adjuvant, an immunological agent that can enhance immune responses, with the current vaccine formulation. Here, we used the murine model to review the effects of adjuvants on the antibody response to influenza vaccines in aged mice. Since adjuvants can enhance the production of important inflammatory cytokines and activation of dendritic cells, the stimulation of these cells are boosted to increase the effectiveness of the influenza vaccine in aged mice which would hopefully translate to the elderly.

Whole-genome sequences of two influenza A(H3N2)virus strains isolated from Qinghai,China

Influenza A(H3N2)virus has a faster evolution rate than other types of influenza viruses.In this study,whole genome sequencing was performed to better understand themolecular evolution of influenzaH3N2 and the protective effect of influenza virus vaccine in Qinghai Province,China,in 2017.Complete sequences of eight gene segments of two seasonal influenza H3N2 isolates were sequenced and analyzed using DNASTAR and MEGA 6.06 software.Additionally,the three-dimensional structure of the HA protein was predicted using the SWISS-MODEL server.Phylogenetic and amino acid sequence analysis revealed that two Qinghai H3N2 isolates were typical low-pathogenic influenza viruses,and were relatively closely related to the 2016–2017 vaccine strain,3C.2a-A/Hong Kong/4801/2014.The presence of several antigenic site substitutions(T131K,G/R142K,K160T and R261Q in the HA protein)were specific for the two Qinghai H3N2 virus strains.In addition,amino acid substitution of K160T at the glycosylation site of HA and H75P in PB1-F2 in Qinghai isolatesmight affect the antibody binding ability and virulence of the influenza virus.The presence of several antigenic site mutations in the Qinghai H3N2 isolates confirmed the evolution of circulating H3N2 strains.

Adjuvant-attenuated symptom severity of influenza infections in vaccinated children

Background:Young children are at high risk for developing complications of influenza,as well as severe clinical presentation of disease.Vaccination provides direct protection and reduces symptom severity in breakthrough in-fections.We assessed whether adjuvanted trivalent seasonal influenza vaccine is associated with symptom severity in children who developed laboratory-confirmed influenza,as compared to children who received quadrivalent inactivated influenza.Methods:A cluster randomized controlled trial of influenza vaccines in Canadian Hutterite colonies was conducted from the 2016-2017 to the 2018-2019 influenza season.Children were vaccinated with either quadrivalent inactivated influenza vaccine(QIV),or the MF59 adjuvanted trivalent influenza vaccine(aTIV).We assessed children who developed PCR-confirmed influenza infection for symptom severity outcomes using multivariable generalized negative binomial regression.Results:Among vaccinated children,49 infections were observed across 1779 person-days.Vaccine formulation(aTIV vs QIV)was not significantly associated with composite symptom outcomes,including total number of symptoms or total duration of symptom presentation(p>0.05 for all outcomes).Receipt of aTIV vaccination was significantly associated with attenuation of fever,with an estimated 74%reduction in fever severity.In influenza A type infections,adjuvanted vaccination was significantly associated with reduced systemic symptoms(incidence rate ratios:0.16,95%confidence intervals:0.03,0.64,p=0.01).No associations were observed between vaccine formulation and symptom severity in influenza B infections.Conclusions:In vaccinated children who develop an influenza infection,vaccine formulation was associated with attenuated fever severity,leading to reduced systemic symptoms.In influenza A infections,adjuvanted vaccination was significantly associated with reduced systemic symptoms.

Prevalence and factors associated with pentavalent vaccination:a cross-sectional study in Southern China

Background Immunization is one of the most far-reaching and cost-effective strategies for promoting good health and saving lives.A complex immunization schedule,however,may be burdensome to parents and lead to reduced vaccine compliance and completion.Thus,it is critical to develop combination vaccines to reduce the number of injections and simplify the immunization schedule.This study aimed to investigate the current status of the pentavalent diphtheria-tetanus-acellular pertussis inactivated poliomyelitis andHaemophilus influenzae type B conjugate(DTaP-IPV/Hib)vaccination in Southern China as well as explore the factors in the general population associated with uptake and the differences between urban and rural populations.Methods A cross-sectional study was conducted with recently enrolled kindergarten students in Hainan Province between December 2022 and January 2023.The study employed a stratified multistage cluster random sampling method.Information regarding the demographic characteristics and factors that influence decisions were collected from the caregivers of children via an online questionnaire.Multivariate logistic regression was used to determine the factors associated with the status of DTap-IPV/Hib vaccinations.Results Of the 4818 valid responses,95.3%of children were aged 3-4 years,and 2856(59.3%)held ruralhukou.Coverage rates of the DTaP-IPV/Hib vaccine,from 1 to 4 doses,were 24.4%,20.7%,18.5%,and 16.0%,respectively.Caregivers who are concerned about vaccine efficacy[adjusted odds ratio(aOR)=1.53,95%confidence interval(CI):1.30-1.79],the manufacturer(aOR=2.05,95%CI:1.69-2.49),and a simple immunization schedule(aOR=1.26,95%CI:1.04-1.54)are factors associated with a higher likelihood of vaccinating children against DTaP-IPV/Hib.In addition,caregivers in urban areas showed more concern about the vaccine price(P=0.010)and immunization schedule(P=0.022)in regard to vaccinating children.Conclusions The DTaP-IPV/Hib vaccine coverage rate in Hainan Province remains low.Factors such as lower socioeconomic status,cultural beliefs,concerns about vaccine safety,and cost may hinder caregivers from vaccinating their children.Further measures,such as health education campaigns to raise knowledge and awareness,and encouragement of domestic vaccine innovation,which would reduce out-of-pocket costs,could be implemented to improve the coverage of DTap-IPV/Hib vaccination.