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1.
Abelin A  Colegate T  Gardner S  Hehme N  Palache A 《Vaccine》2011,29(6):1135-1138
As A(H1N1) influenza enters the post-pandemic phase, health authorities around the world are reviewing the response to the pandemic. To ensure this process enhances future preparations, it is essential that perspectives are included from all relevant stakeholders, including vaccine manufacturers. This paper outlines the contribution of R&D-based influenza vaccine producers to the pandemic response, and explores lessons that can be learned to improve future preparedness.The emergence of 2009 A(H1N1) influenza led to unprecedented collaboration between global health authorities, scientists and manufacturers, resulting in the most comprehensive pandemic response ever undertaken, with a number of vaccines approved for use three months after the pandemic declaration. This response was only possible because of the extensive preparations undertaken during the last decade.During this period, manufacturers greatly increased influenza vaccine production capacity, and estimates suggest a further doubling of capacity by 2014. Producers also introduced cell-culture technology, while adjuvant and whole virion technologies significantly reduced pandemic vaccine antigen content. This substantially increased pandemic vaccine production capacity, which in July 2009 WHO estimated reached 4.9 billion doses per annum. Manufacturers also worked with health authorities to establish risk management plans for robust vaccine surveillance during the pandemic. Individual producers pledged significant donations of vaccine doses and tiered-pricing approaches for developing country supply.Based on the pandemic experience, a number of improvements would strengthen future preparedness. Technical improvements to rapidly select optimal vaccine viruses, and processes to speed up vaccine standardization, could accelerate and extend vaccine availability. Establishing vaccine supply agreements beforehand would avoid the need for complex discussions during a period of intense time pressure.Enhancing international regulatory co-operation and mutual recognition of approvals could accelerate vaccine supply, while maintaining safety standards. Strengthening communications with the public and healthcare workers using new approaches and new channels could help improve vaccine uptake. Finally, increasing seasonal vaccine coverage will be particularly important to extend and sustain pandemic vaccine production capacity.  相似文献   

2.
In June 2009, WHO declared the maximum phase alert against H1N1 pandemic flu. Health care workers (HCWs) are considered a strategic target for prevention of the occurrence of H1N1 influenza since they had the greatest risk of acquiring infection. The objectives of our study were (1) identifying the uptake of influenza A(H1N1) 2009 monovalent vaccine by primary health care workers in the southern part of Cordoba, and (2) reporting of the adverse events occurred after vaccination. We followed 240 HCWs in 12 primary health care centres at southern part of Cordoba for vaccine uptake and the occurrence of adverse events. The coverage rate with H1N1 vaccine was 20.5% which was lower compared to seasonal influenza vaccination rate 44.2% in 2009. Males had higher H1N1 vaccination rate compared to females with no significant difference. Senior HCWs complied more with seasonal influenza vaccine while this finding was not consistent with H1N1 vaccination. Multivariate analysis showed that the only independent variable that affected H1N1 vaccine was the compliance to the seasonal flu vaccine in the past three years with OR 5.1 and 95% CI (2.4-10.8). Adverse events occurred among 26.5% of those who complied with H1N1 vaccination. Those were local pain, irritation and induration at site of injection (38.5%), fever (15.4%), fever cough and rhinorrhea (15.4%) generalized pain and lumber pains (23.1%). The low vaccination rate in this study is consistent with previous studies done in many parts of the world and in Spain. Further studies should be done to explore the factors that hindered the uptake and resistance of HCWs to vaccination to H1N1 vaccine.  相似文献   

3.
4.
We evaluated the efficacy and tolerability of a single dose of the split virion AS03-adjuvanted pandemic H1N1 influenza vaccine (A/California/7/2009) in 84 HIV-1 infected individuals. Antibody titers were determined by hemagglutination inhibition assay and by microneutralization. Vaccine was well tolerated. At 21 days post vaccination, 56 (67%) patients had seroconverted. There was no correlation between baseline CD4 cell count (p = 0.539) or HIV viral load (p = 0.381) and immune response. Other vaccine strategies should be evaluated in this HIV population, to improve response rates.  相似文献   

5.
《Vaccine》2023,41(38):5592-5602
There is a major unmet need for strategies to improve the immunogenicity and effectiveness of pandemic influenza vaccines, particularly in poor responder populations such as neonates. Recombinant protein approaches to pandemic influenza offer advantages over more traditional inactivated virus approaches, as they are free of problems such as egg adaptation or need for high level biosecurity containment for manufacture. However, a weakness of recombinant proteins is their low immunogenicity. We asked whether the use of an inulin polysaccharide adjuvant (Advax) alone or combined with a TLR9 agonist (CpG55.2) would enhance the immunogenicity and protection of a recombinant hemagglutinin vaccine against H7N9 influenza (rH7HA), including in neonatal mice. Advax adjuvant induced predominantly IgG1 responses against H7HA, whereas Advax-CpG55.2 adjuvant also induced IgG2a, IgG2b and IgG3 responses, consistent with the TLR9 agonist component inducing a Th1 bias. Advax-CpG55.2 adjuvanted rH7HA induced high serum neutralizing antibody titers in adult mice. In newborns it similarly overcame immune hypo-responsiveness and enhanced serum anti-rH7HA IgG levels in 7-day-old BALB/C and C57BL/6 mice. Immunized adult mice were protected against a lethal H7N9 virus challenge. When formulated with Advax-CpG55.2 adjuvant, greater protection was seen with rH7HA than with inactivated H7 whole virus antigen. Advax-CpG55.2 adjuvanted rH7HA represents a promising influenza vaccine platform for further development.  相似文献   

6.
Influenza vaccination recommendations are traditionally met with low compliance by healthcare workers (HCWs). The aim of this study is to analyze influenza vaccination among HCWs following a vaccination strategy characterized by an increased effort to maximize the hospital vaccination rate. For this, 2009-2010 seasonal and pandemic influenza vaccination rates among 2739 HCWs at a tertiary university hospital were evaluated. The seasonal influenza vaccination rate was 26.7% (48.3% increase vs. 2008-2009, p = 0.0000), and 14.8% in the case of pandemic influenza. HCWs with direct patient contact showed similar seasonal (25.7%) and pandemic (15.4%) influenza vaccination rates compared to the overall rates. Physician vaccination displayed the highest rate, showing significant differences vs. total rate (38.3%, p = 0.0007 for seasonal, and 32.2%, p = 0.0000 for pandemic influenza). The areas in which the vaccination strategy was most active reflected a significant increase (32.6%, p = 0.0056 for seasonal, and 25.2%, p = 0.0000 for pandemic influenza). It therefore appears that more active campaigns might increase influenza vaccination among HCWs.  相似文献   

7.
Wu J  Zhong X  Li CK  Zhou JF  Lu M  Huang KY  Dong M  Liu Y  Luo FJ  Du N  Chui C  Liu LQ  Smith NM  Li B  Shi NM  Song LF  Gao Y  Wang DY  Wang X  Zhu WF  Yan Y  Li Z  Chen JT  McMichael AJ  Yin WD  Xu XN  Shu Y 《Vaccine》2011,29(5):1009-1016
A randomized clinical trial was conducted to assess whether the immunogenicity of seasonal and pandemic (H1N1/09) influenza vaccines is affected by the order of vaccine administration. 151 healthy adult volunteers were randomized into three groups. All groups received one dose (15 μg haemagglutinin) each of a pandemic H1N1 vaccine and a seasonal trivalent vaccine. Group 1 received the pandemic H1N1 vaccine first, followed by the seasonal vaccine 21 days later. Group 2 received vaccinations in vice versa and Group 3 received both vaccines simultaneously. Post-vaccination blood samples were collected to determine the immunogenicity by hemagglutination-inhibition (HI), microneutralization (MN), and B cell ELISPOT assays. All three vaccination strategies were well-tolerated and generated specific immune responses. However, we found a significant difference in magnitude of antibody responses to pandemic H1N1 between the three groups. Pre- or co-vaccination with the seasonal flu vaccine led to a significant reduction by 50% in HI titre to pandemic H1N1 virus after pandemic vaccination. Pre- or co-vaccination of pandemic H1N1 vaccine had no effect on seasonal flu vaccination. MN and ELISPOT assays showed a similar effect. Vaccination with pandemic H1N1 vaccine first is recommended to avoid an associated inhibitory effect by the seasonal trivalent flu vaccine. Clinical_Trials identifier: NCT01008137.  相似文献   

8.
Hidiroglu S  Ay P  Topuzoglu A  Kalafat C  Karavus M 《Vaccine》2010,28(51):8120-8124
During the H1N1 pandemic, most healthcare workers in Turkey were not willing to take up the vaccine. This qualitative study aims to explore the factors that lead to vaccination resistance among a group of primary healthcare workers in Istanbul. Data were collected through focus group discussions. Thematic content analysis was conducted. All participants considered themselves at risk for infection, yet most of them were not vaccinated. Only persons with a "poor" immune system were considered by the respondents at risk for severe disease and death. Health personnel mostly did not realize their potential role in the transmission of influenza to patients. The decision of vaccination was dependent on the information source. The personnel who depended mainly on the media either did not accept vaccination or was undecided. They believed that the vaccine went through an accelerated authorization procedure. Yet the ones who accepted vaccination relied mostly on evidence-based sources and accessed information from the guidelines of the Ministry of Health, Professional Medical Associations and the World Health Organization. Social networks were also influential factors in the decision-making process. It is important to empower healthcare workers through supporting the skills of acquiring and using evidence-based information. This is particularly important for physicians who also serve as opinion leaders.  相似文献   

9.
Influenza virus infections continue to cause production losses in the agricultural industry in addition to being a human public health concern. The primary method to control influenza is through vaccination. However, currently used killed influenza virus vaccines must be closely matched to the challenge virus. The ability of an elastase-dependent live attenuated influenza A virus was evaluated to protect pigs against the pandemic H1N1 2009 influenza virus. Pigs vaccinated intranasally or intratracheally with the elastase-dependent swine influenza virus (SIV) vaccine had significantly reduced macroscopic and microscopic lung lesions and lower viral loads in the lung and in nasal swabs. Thus, elastase-dependent SIV mutants can be used as live-virus vaccines against swine influenza in pigs. In addition, low levels of cross-neutralizing antibodies to H1N1 2009 were elicited prior to challenge by the swine adapted H1N1 avian strain vaccine.  相似文献   

10.
Neutralizing antibody titers were determined before and after a single dose of pandemic (H1N1) 2009 influenza vaccine in HIV-1-positive Japanese adults in the first season of the pandemic and in those in the second season who had already received the vaccine in the first season. The antibody response rate at 2-month post-vaccination increased significantly from 49.0% (50/102, 95%CI: 39.0-59.1%) in the 2009/2010 season to 66.7% (42/63, 95%CI: 53.7-78.1%) in the 2010/2011 season. Geometric mean antibody titers (fold dilution) at baseline, at 2 months, and at 4 months also increased significantly from 4.4 (95%CI: 3.3-5.7), 19.0 (95%CI: 13.4-26.8) and 13.7 (95%CI: 9.3-20.2), respectively, in the 2009/2010 season to 8.3 (95%CI: 5.8-11.7), 47.0 (95%CI: 32.2-68.6) and 38.2 (95%CI: 23.8-61.4), respectively, in the 2010/2011 season. Although the vaccine response was low in the first season, it was improved in the second season.  相似文献   

11.
Coverage of the HCWs as target population is one of the important determinants for the impact of vaccination. To determine the vaccination against the pandemic influenza A/H1N1 among HCWs, we conducted a cross-sectional questionnaire survey in a public hospital in Istanbul from December 7 to December 22, 2009. Out of total 941 HCWs 718 (76.3%) completed the questionnaires. Nearly one-fourth (23.1%) of the participants were vaccinated against pandemic influenza A/H1N1. Occupation (being a doctor), receiving seasonal influenza vaccine in 2009, agreement with safety of pandemic influenza A/H1N1 vaccine and being comprehend that HCWs have a professional responsibility for getting vaccinated was the strongest independent predictive factor for accepting the pandemic influenza A/H1N1 vaccine (p < .0001). The most frequent reasons for refusing pandemic vaccine were fear of side effects and doubts about vaccine efficacy. Among HCWs 59.6% were recommending pandemic influenza vaccination to a patient even if indicated. In conclusion vaccination against pandemic influenza A/H1N1 is insufficient among HCWs. Misinformed or inadequately informed HCWs are important barrier to pandemic influenza vaccine coverage of the general public also. Educational campaigns concerning HCWs should include evidence based and comprehensible information about possible adverse effects and their incidence besides the advantages of vaccine.  相似文献   

12.
《Vaccine》2016,34(33):3757-3763
Eurasian avian-like H1N1 (EA H1N1) swine influenza viruses are prevalent in pigs in Europe and Asia, but occasionally cause human infection, which raises concern about their pandemic potential. Here, we produced a whole-virus inactivated vaccine with an EA H1N1 strain (A/swine/Guangxi/18/2011, SW/GX/18/11) and evaluated its efficacy against homologous H1N1 and heterologous H1N1 and H1N2 influenza viruses in mice. A strong humoral immune response, which we measured by hemagglutination inhibition (HI) and virus neutralization (VN), was induced in the vaccine-inoculated mice upon challenge. The inactivated SW/GX/18/11 vaccine provided complete protection against challenge with homologous SW/GX/18/11 virus in mice and provided effective protection against challenge with heterologous H1N1 and H1N2 viruses with distinctive genomic combinations. Our findings suggest that this EA H1N1 vaccine can provide protection against both homologous H1N1 and heterologous H1N1 or H1N2 virus infection. As such, it is an excellent vaccine candidate to prevent H1N1 swine influenza.  相似文献   

13.
The purpose of this study was to evaluate the coverage rates for influenza vaccination among health-care personnel (HCP), and if the reasons for accepting influenza vaccine by HCP and the frequency of vaccine-related adverse events (AEs) in 2010-2011 were different compared to 2009-2010. The AEs were detected by telephoning the worker one week after the vaccination. The coverage for seasonal vaccination in 2009-2010 was 31.0%, whereas that for 2009 pandemic influenza (H1NI) was 22.2% and 24.4% (p < 0.05) in 2010-2011. The most frequent reason for being vaccinated during the three campaigns was to “protect my health”. Over 80.5% of the HCP reported 2009 pandemic influenza (H1N1) vaccine-related AEs compared to the 25.3% and 25.4% reporting seasonal vaccine-related AEs in 2009-2010 and 2010-2011 respectively (p < 0.05). None of the AEs were severe. Specific measures should be implemented in our country to recover and improve poor vaccination coverage.  相似文献   

14.
Several limitations of the use of embryonated eggs and the threat of pandemics have highlighted the need for other platforms for the production of influenza vaccines. We report the indigenous development and pre-clinical testing of an MDCK-based H1N1 pandemic influenza vaccine HNVAC from India. The cell bank and virus seed were characterized extensively. The cells were characterized by PCR, electron microscopy, and karyotyping, and found to be of female canine epithelial origin. The virus was confirmed by neutralization, haemagglutination inhibition, neuraminidase inhibition, and PCR and nucleotide sequencing. Adventitious agent testing was performed by both in vitro and in vivo studies. The in vitro studies included culturing, haemadsorption, haemagglutination, PCR and RT-PCR, whereas in vivo studies included passage in embryonated eggs and in laboratory animals. Both cell bank and virus seed were free of adventitious agents. MDCK cell lysates as well as cellular DNA did not produce tumours in newborn or adult laboratory animals. The bioprocess parameters were standardized to recover antigen with minimal levels of process-related impurities. The vaccine bulk was tested for the presence of specific antigen, and quantified by single radial immunodiffusion. Finally, non-adjuvanted and aluminium hydroxide adjuvanted vaccine formulations were found to be safe in preclinical toxicity studies in mice, rats, guinea pigs and rabbits, and immunogenic in mice and rabbits. This is the first and only cell culture-based influenza vaccine platform developed in any developing country.  相似文献   

15.

Background

Immune responses to novel pandemic influenza vaccines may be influenced by previous exposure to antigenically similar seasonal strains.

Methods

An open-label, randomized, phase I/II study was conducted to assess the immunogenicity and safety of a non-adjuvanted, inactivated whole-virus H1N1 A/California/07/2009 vaccine. 408 subjects were stratified by age (18–59 and >60 years) and randomized 1:1 to receive two vaccinations with either 3.75 or 7.5 μg hemagglutinin antigen 21 days apart. Safety, immunogenicity and the influence of seasonal influenza vaccination and antibody cross-reactivity with a seasonal H1N1 strain was assessed.

Results

A single vaccination with either dose induced substantial increases in H1N1 A/California/07/2009 hemagglutination inhibition (HI) and neutralizing (MN) antibody titers in both adult and elderly subjects. A single 7.5 μg dose induced seroprotection rates of 86.9% in adults and 75.2% in elderly subjects. Two 7.5 μg vaccinations induced seroprotection rates in adult and elderly subjects of 90.9% and 89.1%, respectively. The robust immune response to vaccination was confirmed by analyses of neutralizing antibody titers. Both HI and MN antibodies persisted for ≥6 months post-vaccination. Between 34% and 49% of subjects had seroprotective levels of H1N1 A/California/07/2009 antibodies at baseline. Higher baseline HI titers were associated with receipt of the 2008–09 or 2009–10 seasonal influenza vaccine. High baseline A/California/07/2009 neutralizing antibody titers were also associated with high baseline titers against A/New Caledonia/20/99, a seasonal H1N1 strain which circulated and was included in the seasonal vaccine from 2000–01 to 2006–07. Pre-adsorption with A/H1N1/New Caledonia/20/99 antigen reduced A/H1N1/California/07/2009 baseline titers in 55% of tested sera. The vaccine was well tolerated with low rates of fever.

Conclusions

A whole-virus H1N1 A/California/07/2009 vaccine was safe and well tolerated and a single dose induced substantial immune responses similar to seasonal influenza vaccines, probably due to immunological priming by previous seasonal influenza vaccines or infections.  相似文献   

16.
We conducted a multi-center, randomized, laboratory-blinded clinical trial in 185 healthy adults (<60 years) and 107 elders (>60 years) to examine the immunogenicity and safety of different doses of an inactivated, monovalent, non-adjuvanted, split vaccine against the 2009 pandemic influenza A (H1N1) virus. The 186 adults were assigned to three treatment groups, i.e., one 15 μg hemagglutination (HA) antigen dose, two 15 μg or 30 μg HA doses in 3 weeks apart, and the 107 elders were treated with two 15 μg or 30 μg doses in 3 weeks apart. Prior to the vaccination, 4.8% subjects had hemagglutination-inhibition (HAI) antibody titers of 1:40 or more. By day 21 post-vaccination of one dose of 15 μg HA, the seroprotective rate was 95.1% and 75.5% in subjects <60 and >65 years of age, respectively; by day 21 post the second 15 μg HA dose, the seroprotective rates were 93.2% and 73.1%, respectively. The seroprotective rates for recipients of 30 μg HA antigen by day 21 were 95.2% for subjects <60 years and 81.1% for subjects >65 years of age, that was boosted to 98.3% and 80.4%, respectively with a second dose of 30 μg HA antigen. No vaccine-related serious adverse events occurred. The data indicated a single 15 μg HA dose of the vaccine induced a protective immune response in most adults, including the elders >60 years of age, and a booster dose at the third week did not render a higher level of antibody response.  相似文献   

17.
The rapid evolution, genetic diversity, broad host range, and increasing human infection with avian influenza A (H5N1) viruses highlight the need for an efficacious cross-clade vaccine. Using the ferret model, we compared induction of cross-reactive immunity and protective efficacy of three single-clade H5N1 vaccines and a novel multiple-clade H5N1 vaccine, with and without MF59 adjuvant. Reverse genetics (rg) was used to generate vaccine viruses containing the hemagglutinin (HA) and neuraminidase genes of wild-type H5N1 viruses. Ferrets received two doses of inactivated whole-virus vaccine separated by 3 weeks. Single-clade vaccines (7.5 μg HA per dose) included rg-A/Vietnam/1203/04 (clade 1), rg-A/Hong Kong/213/03 (clade 1), and rg-A/Japanese White Eye/Hong Kong/1038/06 (clade 2.3). The multiple-clade vaccine contained 3.75 μg HA per dose of each single-clade vaccine and of rg-A/Whooper Swan/Mongolia/244/05 (clade 2.2). Two doses of vaccine were required to substantially increase anti-HA and virus neutralizing antibody titers to H5N1 viruses. MF59 adjuvant enhanced induction of clade-specific and cross-clade serum antibody responses, reduced frequency of infection (as determined by upper respiratory tract virus shedding and seroconversion data), and eliminated disease signs. The rg-A/Hong Kong/213/03 vaccine induced the highest antibody titers to homologous and heterologous H5N1 viruses, while rg-A/Japanese White Eye/Hong Kong/1038/06 vaccine induced the lowest. The multiple-clade vaccine was broadly immunogenic against clade 1 and 2 viruses. The rg-A/Vietnam/1203/04 vaccine (the currently stockpiled H5N1 vaccine) most effectively reduced upper respiratory tract virus shedding after challenge with clade 1 and 2 viruses. Importantly, all vaccines protected against lethal challenge with A/Vietnam/1203/04 virus and provided cross-clade protection.  相似文献   

18.
In order to evaluate the immunogenicity, safety and tolerability of the 2009 A/H1N1 MF59-adjuvanted influenza vaccine administered sequentially or simultaneously with seasonal virosomal-adjuvanted influenza vaccine to HIV-infected children and adolescents, 36 HIV-infected children and adolescents, and 36 age- and gender-matched healthy controls were randomised 1:1 to receive the pandemic vaccine upon enrolment and the seasonal vaccine one month later, or to receive the pandemic and seasonal vaccines simultaneously upon enrolment. Seroconversion and seroprotection rates against the pandemic influenza A/H1N1 virus were 100% two months after vaccine administration in both groups, regardless of the sequence of administration. Geometric mean titres against pandemic and seasonal antigens were significantly higher when the seasonal and pandemic vaccines were administered simultaneously than when the seasonal vaccine was administered alone. Local and systemic reactions were mild and not increased by simultaneous administration. In conclusion, the 2009 pandemic influenza A/H1N1 MF59-adjuvanted vaccine is as immunogenic, safe and well tolerated in HIV-infected children and adolescents as in healthy controls. Its simultaneous administration with virosomal-adjuvanted seasonal antigens seems to increase immune response to both pandemic and seasonal viruses with the same safety profile as that of the pandemic vaccine alone. However, because this finding cannot be clearly explained by an immunological viewpoint, further studies are needed to clarify the reasons of its occurrence.  相似文献   

19.
The advent of the H1N1 influenza pandemic (pH1N1) in 2009 triggered the rapid production of pandemic influenza vaccines, since seasonal influenza vaccines were expected and demonstrated not to provide significant cross-protection against the newly emerged pandemic virus. To increase vaccine production capacity and further evaluate the effectiveness of different candidate pandemic influenza vaccines, the World Health Organization stimulated the evaluation of different vaccination concepts including the use of live attenuated influenza vaccines (LAIVs). Therefore, we have immunized ferrets intranasally with a single dose of pH1N1-LAIV from different manufacturers. They all induced adequate serum HI antibody titers in the ferrets and protected them against intratracheal wild-type pH1N1 virus challenge: pH1N1 virus replication in the upper respiratory tract and lungs was reduced and no disease signs or severe broncho-interstitial pneumonia were observed in any of the vaccinated ferrets. These data together with the relatively efficient production process emphasize the potential of the LAIV concept for pandemic preparedness.  相似文献   

20.
DiBiase LM  Davis SE  Rosselli R  Horney J 《Vaccine》2011,29(23):3969-3976

Introduction

Effective conduct of vaccination campaigns by public health authorities can reduce morbidity and mortality associated with influenza. The emergence of the pandemic H1N1 influenza in April 2009 resulted in an unprecedented vaccination campaign in the US during the 2009-2010 influenza season. The variety of methods local health departments (LHDs) utilized to cope with a mismatch between public demand and supply and ever-changing guidelines have gone unexamined thus far. The purpose of this research is to identify and share lessons learned related to H1N1 influenza vaccination activities at LHDs.

Methods

In April 2010, a comprehensive survey was developed to evaluate 2009-10 LHD H1N1 vaccination practices and document lessons learned. A stratified random sample was selected from NC's 85 LHDs. Interviews were conducted with key personnel involved in LHD vaccination campaigns. Results were analyzed to identify quantitative trends and qualitative themes.

Results

Twenty-five of 26 LHDs (96% response rate) participated in our survey. Each LHD utilized a different approach to address the challenges they faced during their H1N1 vaccination campaign. Variation between LHDs was found in terms of the types of vaccine-dispensing methods implemented and in the selection of outside organizations LHDs partnered with to assist with vaccinations.

Conclusion

Having a Continuity of Operations Plan (COOP) and pandemic influenza plan, hiring temporary staff, building on existing community partnerships, implementing a variety of vaccination strategies and using a variety of sites are strategies that will help LHDs deal more effectively with challenges posed by future pandemics.  相似文献   

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