Differential durability of immune responses to measles and mumps following MMR vaccination

The development and wide-spread use of mumps vaccine resulted in a dramatic and sustained decrease in the incidence of mumps disease; however, since 2000, an increase in the size and number of mumps outbreaks in the United States and other countries has sparked renewed interest in the durability of mumps-specific immunity elicited by mumps vaccination. The most likely explanation for mumps cases in previously immunized persons may be secondary vaccine failure, or waning immunity. In the current study, we examined changes in markers of measles and mumps immunity at two timepoints, approximately 7 and 17 years after two-dose MMR-II® vaccination, in a cohort of 98 healthy adults.Our results indicate that mumps IgG titers exhibited a large and significant decline during this time period, while mumps neutralizing Ab titers were relatively stable. There was a similar discrepancy with measles-specific immune responses. For both pathogens, neutralizing antibody titers were fairly low and, given the length of time since vaccination, may have already declined. These data suggest that specific immune outcomes may wane at different rates and highlight our currently incomplete understanding of protective immune responses to mumps and measles.     

Measles,mumps, and rubella antibody patterns of persistence and rate of decline following the second dose of the MMR vaccine

BackgroundAntibodies to measles, mumps, and rubella decline 3% per year on average, and have a high degree of individual variation. Yet, individual variations and differences across antigens are not well understood. To better understand potential implications on individual and population susceptibility, we reanalyzed longitudinal data to identify patterns of seropositivity and persistence.MethodsChildren vaccinated with the second dose of measles, mumps, rubella vaccine (MMR2) at 4–6 years of age were followed up to 12 years post-vaccination. The rates of antibody decline were assessed using regression models, accounting for differences between and within subjects.ResultsMost of the 302 participants were seropositive throughout follow-up (96% measles, 88% mumps, 79% rubella). The rate of antibody decline was associated with MMR2 response and baseline titer for measles and age at first dose of MMR (MMR1) for rubella. No demographic or clinical factors were associated with mumps rate of decline. One month post-MMR2, geometric mean titer (GMT) to measles was high (3892 mIU/mL), but declined on average 9.7% per year among those with the same baseline titer and <2-fold increase post-MMR2. Subjects with ≥2-fold experienced a slower decline (≤7.4%). GMT to rubella was 149 one month post-MMR2, declining 2.6% and 5.9% per year among those who received MMR1 at 12–15 months and >15 months, respectively. GMT to mumps one month post-MMR2 was 151, declining 9.2% per year. Only 14% of subjects had the same persistence trends for all antigens.ConclusionsThe rate of antibody decay varied substantially among individuals and the 3 antigen groups. A fast rate of decline coupled with high variation was observed for mumps, yet no predictors were identified. Future research should focus on better understanding waning titers to mumps and its impacts on community protection and individual susceptibility, in light of recent outbreaks in vaccinated populations.     

Associations between race,sex and immune response variations to rubella vaccination in two independent cohorts

Introduction

Immune response variations after vaccination are influenced by host genetic factors and demographic variables, such as race, ethnicity and sex. The latter have not been systematically studied in regard to live rubella vaccine, but are of interest for developing next generation vaccines for diverse populations, for predicting immune responses after vaccination, and for better understanding the variables that impact immune response.

Methods

We assessed associations between demographic variables, including race, ethnicity and sex, and rubella-specific neutralizing antibody levels and secreted cytokines (IFNγ, IL-6) in two independent cohorts (1994 subjects), using linear and linear mixed models approaches, and genetically defined racial and ethnic categorizations.

Results

Our replicated findings in two independent, large, racially diverse cohorts indicate that individuals of African descent have significantly higher rubella-specific neutralizing antibody levels compared to individuals of European descent and/or Hispanic ethnicity (p < 0.001).

Conclusion

Our study provides consistent evidence for racial/ethnic differences in humoral immune response following rubella vaccination.     

Universal rubella vaccination programme and maternal rubella immune status: A tale of two systems

Maternal rubella status was compared between local residents with non-residents who delivered in our hospital during 1998–2008. Among the 60,822 women, non-immunity was more common in the non-residents (19.9% versus 8.1%, P < 0.001). Significant difference and positive correlation with age and parity were found for both groups, but a significant inverse correlation with year-of-birth was found only in the residents. Regression analysis confirmed that birth after 1970 was associated with reduced odds of non-immunity, which indicated that the rubella vaccination programme, introduced since 1978, has succeeded in reducing the incidence of non-immunity to <5% in the youngest generation.     

Age-stratified seroprevalence of measles, mumps and rubella (MMR) virus infections in Switzerland after the introduction of MMR mass vaccination

We have performed age-stratified seroprevalence studies for MMR to evaluate these vaccinations. Serum samples submitted for diagnostic testing were randomly selected for unlinked anonymous panels. IgG antibodies were tested by ELISA and indirect immunofluorescence. In the vaccination cohort (age 1.5 to 6.5 years), seroprevalence attained 80%. For measles and mumps it continued to increase to 95%, while for rubella it declined transiently to 60% between 7 and 12 years of age. We observed no differences according to gender in any age group in 1991--1992. (Semi)quantitative values of the IgG antibodies against all three viruses increased during adolescence, suggesting wild virus circulation. In 1992, MMR vaccination has reached < 80% of the children during their second year of age. Due to previous monovalent measles and mumps vaccinations in pre-school children and due to endemic and epidemic activity, particularly of mumps virus, a trough of the seroprevalence in adolescents was evident only for rubella. MMR vaccination campaigns performed at school since 1987 have increased seroprevalence in this population segment and have probably over-compensated for the expected shift to the right of the seroprevalence curves. A more compulsive implementation of the recommended childhood vaccination schedule and continued efforts at catchup vaccinations during school age especially for rubella are necessary to avoid the accumulation of susceptible young adults during the forthcoming decades.     

Immunity to rubella before and after vaccination against measles, mumps and rubella (MMR) at 12 years of age of the first generation offered MMR vaccination in Sweden at 18 months

In 1982, a two-dose programme of vaccination against measles, mumps and rubella (MMR) at the ages of 18 months and 12 years was introduced in Sweden. In 1992–1993, the first group of children vaccinated at 18 months reached the age of 12, i.e. the time for a second dose. In connection with this 12-year vaccination, 376 children were recruited, investigated concerning earlier MMR vaccination and bled prior to and 2 months after the immunization. Two hundred and twenty of them had a documented, earlier MMR vaccination and 156 had not. The latter were classified as unvaccinated. The antibody status against rubella was measured by the haemolysis-in-gel method. Prior to the present vaccination, 3% of the earlier vaccinated group totally lacked any sign of antibodies. In the presumably unvaccinated group, this figure was 76%. After the vaccination all children showed signs of antibody acitivity and all reached the antibody level of ≥15 international units, i.e. in our tests a zone dia. of approx 8 mm. However, the secondly vaccinated children ended up with a mean antibody level of 10.7 mm which was slightly lower than the level, i.e. 11.0 mm of those lacking earlier vaccination history and prevaccination seronegative. The earlier unvaccinated but pre-immune children reached a mean level of 11.2 mm. In general, those with relatively high, pre-vaccination, antibody levels reacted less to the booster than those with low or no pre-vaccination immunity. The booster thus appeared to restore the antibody levels of the low-titre children.     

Pertussis specific cell-mediated immune responses ten years after acellular pertussis booster vaccination in young adults

BackgroundOne of the reasons for pertussis resurgence is waning immunity. Both humoral and cell mediated immunity (CMI) are essential for protection. The aim of this study was to evaluate CMI responses after acellular pertussis vaccination in young adults.MethodsFifty-seven young adults were followed for ten years after a diphtheria-tetanus acellular pertussis (dTpa) booster vaccination. A second booster was administrated at year 10. CMI was determined from peripheral blood mononuclear cells (PBMC) stimulated with vaccine antigens pertussis toxin (PT), filamentous hemagglutinin (FHA) and pertactin (PRN) before and one month after the second vaccination, using proliferation and IFN-γ and IL-17 ELISpot. In addition, the response to ten selected cytokines was measured from 14 subjects.ResultsBefore the booster dose, positive proliferation was recognized in 51%, 53% and 89% of the subjects against PT, PRN and FHA, respectively. One month after, the positivity rate increased to 81%, 81% and 96%. Although the number of IFN-γ and IL-17 secreting cells was increased, the expression of most of the tested cytokines was found to be downregulated. After PT stimulation, only one (7.1%) subject had increased production in all cytokines, whereas six (42.9%) had decreased production of all cytokines. Ten subjects (71.4%) had decreased concentration of IFN-γ, the cytokine important for pertussis protection.ConclusionsCMI persists even when antibodies have decayed, and acellular pertussis vaccine enhances the CMI response. Further studies are needed to illustrate what factors cause the low production of some important cytokines.     

Within-host modeling to measure dynamics of antibody responses after natural infection or vaccination: A systematic review

BackgroundWithin-host models describe the dynamics of immune cells when encountering a pathogen, and how these dynamics can lead to an individual-specific immune response. This systematic review aims to summarize which within-host methodology has been used to study and quantify antibody kinetics after infection or vaccination. In particular, we focus on data-driven and theory-driven mechanistic models.MaterialsPubMed and Web of Science databases were used to identify eligible papers published until May 2022. Eligible publications included those studying mathematical models that measure antibody kinetics as the primary outcome (ranging from phenomenological to mechanistic models).ResultsWe identified 78 eligible publications, of which 8 relied on an Ordinary Differential Equations (ODEs)-based modelling approach to describe antibody kinetics after vaccination, and 12 studies used such models in the context of humoral immunity induced by natural infection. Mechanistic modeling studies were summarized in terms of type of study, sample size, measurements collected, antibody half-life, compartments and parameters included, inferential or analytical method, and model selection.ConclusionsDespite the importance of investigating antibody kinetics and underlying mechanisms of (waning of) the humoral immunity, few publications explicitly account for this in a mathematical model. In particular, most research focuses on phenomenological rather than mechanistic models. The limited information on the age groups or other risk factors that might impact antibody kinetics, as well as a lack of experimental or observational data remain important concerns regarding the interpretation of mathematical modeling results. We reviewed the similarities between the kinetics following vaccination and infection, emphasising that it may be worth translating some features from one setting to another. However, we also stress that some biological mechanisms need to be distinguished. We found that data-driven mechanistic models tend to be more simplistic, and theory-driven approaches lack representative data to validate model results.     

Proteomic assessment of humoral immune responses in smallpox vaccine recipients

The availability of effective smallpox vaccines was a critical element of the successful eradication of smallpox in 1980. Antibody responses play a primary role in protective immunity and neutralizing antibody is an established correlate of protection against smallpox. In this study we used a poxvirus proteome array to assess the antibody response to individual viral proteins in a cohort of 1,037 smallpox vaccine recipients. Several statistically significant differences were observed in the antibody response to immunodominant proteins between men and women, including B5R—a major target of neutralizing antibody in vaccinia immune globulin, and the membrane proteins D8L and A27L, both of which have been used as vaccine antigens providing protection in animal models. We also noted differences across racial/ethnic groups. In this cohort, which consisted of both ACAM2000 and Dryvax recipients, we noted minute differences in the antibody responses to a restricted number of viral proteins, providing additional support for the use of ACAM2000 as a replacement smallpox vaccine. Furthermore, our data indicate that poxvirus proteome microarrays can be valuable for screening and monitoring smallpox vaccine-induced humoral immune responses in large-scale serologic surveillance studies and prove useful in the guidance of developing novel smallpox candidate vaccines.     

The incidence of rubella virus infections in Switzerland after the introduction of the MMR mass vaccination programme

We have collected data on the incidence of rubella in Switzerland from 1987 to 1992 to help evaluating the impact of the measles, mumps and rubella (MMR) mass vaccination programme which started in 1985 in this country. We used detailed informations on samples submitted for diagnostic testing in conjunction with anonymous laboratory notifications to the Swiss Federal Office for Public Health, and data from the Swiss sentinel network of general practitioners to find trends in the incidence of rubella after the introduction of mass vaccination. We observed an unabated seasonal oscillation without decreasing trend during the observation period and were unable to detect a shift in the age distribution of cases. An important proportion of laboratory-confirmed rubella occurred in women of childbearing age. Immigrants from regions with low endemicity of rubella were at increased risk of contracting rubella and transmitting it to their offspring. We conclude, that MMR mass vaccination has not interrupted the circulation of rubella virus in Switzerland, and that improvements in the implementation and surveillance of the MMR vaccination campaign are necessary in order to avoid untoward effects of it.     

Rubella virus-specific humoral immune responses and their interrelationships before and after a third dose of measles-mumps-rubella vaccine in women of childbearing age

In the U.S., measles, mumps, and rubella vaccination is recommended as two vaccine doses. A third dose of measles-mumps-rubella (MMR) vaccine is being administered in certain situations (e.g., identified seronegativity and during outbreaks).We studied rubella-specific humoral immunity (neutralizing antibody, enzyme-linked immunosorbent assay/ELISA IgG titer and antibody avidity) and the frequencies of antigen-specific memory B cells before and after a third dose of MMR-II in 109 female participants of childbearing age (median age, 34.5 years old) from Olmsted County, MN, with two documented prior MMR vaccine doses. The participants were selected from a cohort of 1117 individuals if they represented the high and the low ends of the rubella-specific antibody response spectrum. Of the 109 participants, we identified four individuals (3.67% of all study participants; 7.14% of the low-responder group) that were seronegative at Baseline (rubella-specific ELISA IgG titers <10 IU/mL), suggesting a lack of protection against rubella before receipt of a third MMR vaccine dose. The peak geometric mean neutralizing antibody titer one month following the third dose of MMR vaccine for the cohort was 243 NT₅₀ (CI; 241, 245), which is expected for a cohort with two doses of MMR, and the peak geometric mean IgG titer was 150 IU/mL (CI; 148, 152) with no seronegative individuals at Day 28. One-third of all subjects (31.8% for the neutralizing antibody; 30.8% for the IgG titer) experienced a significant boost (≥4-fold) of antibody titers one month following vaccination. Antibody titers and other tested immune-response variables were significantly higher in the high-responder group compared to the low-responder group. The frequencies of rubella-specific memory B cells were modestly associated with the antibody titers. Our study suggests the importance of yet unknown inherent biologic and immune factors for the generation and maintenance of rubella-vaccine-induced humoral immune responses.     

Associations between markers of cellular and humoral immunity to rubella virus following a third dose of measles-mumps-rubella vaccine

IntroductionRubella virus (RV) was eliminated in the United States in 2004, although a small portion of the population fails to develop long-term immunity against RV even after two doses of the measles-mumps-rubella (MMR) vaccine. We hypothesized that inherent biological differences in cytokine and chemokine signaling likely govern an individual’s response to a third dose of the vaccine.MethodsHealthy young women (n = 97) were selected as study participants if they had either low or high extremes of RV-specific antibody titer after two previous doses of MMR vaccine. We measured cytokine and chemokine secretion from RV-stimulated PBMCs before and 28 days after they received a third dose of MMR vaccine and assessed correlations with humoral immune response outcomes.ResultsHigh and low antibody vaccine responders exhibited a strong pro-inflammatory cellular response, with an underlying Th1-associated signature (IL-2, IFN-γ, MIP-1β, IP-10) and suppressed production of most Th2-associated cytokines (IL-4, IL-10, IL-13). IL-10 and IL-4 exhibited significant negative associations with neutralizing antibody titers and memory B cell ELISpot responses among low vaccine responders.ConclusionIL-4 and IL-10 signaling pathways may be potential targets for understanding and improving the immune response to rubella vaccination or for designing new vaccines that induce more durable immunity.     

Effect of atorvastatin on humoral immune response to 23-valent pneumococcal polysaccharide vaccination in healthy volunteers: The StatVax randomized clinical trial

Background

The immunomodulatory effects of statins on vaccine response remain uncertain. Therefore, the objective of this study was to determine if atorvastatin enhances pneumococcal-specific antibody titer following 23-valent pneumococcal polysaccharide vaccination.

Characterization of the humoral and cellular immune responses against hepatitis C virus core induced by DNA-based immunization

Hepatitis C Virus (HCV) causes most cases of posttransfusion hepatitis. Chronic HCV infection is highly related to chronic hepatitis, cirrhosis and hepatocellular carcinoma. Current therapies are only minimally effective and no vaccine has been developed. DNA-based immunization could be of prophylactic and therapeutic value for HCV infection. By intramuscular inoculation in BALB/c mice with an HCV recombinant plasmid pCI-HCV-C, we found significant levels of IgM antibody, but no significant IgG rise. After boost the immunized mice with recombinant HCV-core protein (cp1-10; 1-164aa), the anticore IgG, verified by Western-blotting, rose rapidly, which was two weeks earlier than that with control plasmid. Spleen cells from pCI-HCV-C immunized mice gave higher proliferation index (PI) than control (P < 0.05). The PI of cp1-10 boosted mice was even higher. Proliferation blocking assay with mAb proved the responding cell to be of CD4+ CD8- phenotype, supporting specific priming of T helper cells. A 51Cr-releasing CTL assay specific for HCV-core was developed, and a specific CTL response against HCV-core was demonstrated in both pCI-HCV-C immunized mice and mice boosted with cp1-10. Strong cytotoxic activity against peptide-pulsed p815 cells (H-2d), but not EL-4 cells (H-2b), suggested MHC class I restriction of the CTL activity. Blocking of CTL with mAb proved the effector cells to be of CD4- CD8+. Three CTL epitopes in HCV-core protein were demonstrated. We failed to detect CTL when immunized only with core protein. The results suggested that vaccination with HCV-core derived DNA sequences could be an effective method to induce humoral and cellular immune responses to HCV.     

HLA genotypes and rubella vaccine immune response: Additional evidence

Recent population-based studies have demonstrated the genetic heritability of rubella vaccine response and assessed that the HLA system may explain about 20% of the inter-individual variance in humoral immune response to this vaccine. Our earlier studies compared HLA allelic associations with rubella vaccine-specific antibodies between two smaller cohorts of healthy Rochester, MN, children (346 and 396 subjects) after two doses of rubella-containing vaccine. This study found that specific HLA alleles were consistently associated with rubella-specific antibody titers (B*27:05, DPA1*02:01, and DPB1*04:01 alleles). The current study examined HLA associations in an independent larger cohort of 1012 healthy San Diego, CA, subjects (age 19–40 years) after rubella vaccine in order to replicate our previous findings in the Rochester subjects. Two HLA associations of comparable magnitudes were consistently observed between B*27:05 (median NT₅₀ Rochester cohort 48.9, p = 0.067; San Diego cohort 54.8, p = 0.047) and DPB1*04:01 (median NT₅₀ Rochester cohort 61.6, p < 0.001; San Diego cohort 70.8, p = 0.084) alleles and rubella virus-neutralizing antibody titers. Additional HLA alleles resulted in consistent effects on IL-6 production in both cohorts, but did not meet criteria for statistical significance. Our data suggest these HLA alleles play a role in rubella vaccine-induced immunity and provide the basis for future studies that may explain the mechanism(s) by which these HLA polymorphisms affect immune responses to rubella vaccine.     

Long-lasting heterologous antibody responses after sequential vaccination with A/Indonesia/5/2005 and A/Vietnam/1203/2004 pre-pandemic influenza A(H5N1) virus vaccines

BackgroundAvian influenza A(H5N1) viruses have caused sporadic infections in humans and thus they pose a significant global health threat. Among symptomatic patients the case fatality rate has been ca. 50%. H5N1 viruses exist in multiple clades and subclades and several candidate vaccines have been developed to prevent A(H5N1) infection as a principal measure for preventing the disease.MethodsSerum antibodies against various influenza A(H5N1) clade viruses were measured in adults by ELISA-based microneutralization and haemagglutination inhibition tests before and after vaccination with two different A(H5N1) vaccines in 2009 and 2011.ResultsTwo doses of AS03-adjuvanted A/Indonesia/5/2005 vaccine induced good homologous but poor heterologous neutralizing antibody responses against different clade viruses. However, non-adjuvanted A/Vietnam/1203/2004 booster vaccination in 2011 induced very strong and long-lasting homologous and heterologous antibody responses while homologous response remained weak in naïve subjects.ConclusionsSequential vaccination with two different A(H5N1) pre-pandemic vaccines induced long-lasting high level cross-clade immunity against influenza A(H5N1) strains, thus supporting a prime-boost vaccination strategy in pandemic preparedness plans.     

Replication of rubella vaccine population genetic studies: Validation of HLA genotype and humoral response associations

Purported genetic associations found in population studies require validation for confirmation. We previously reported rubella vaccine-induced immune responses and HLA associations in 346 adolescents, age 12–18 years (1st cohort), following two doses of a rubella-containing vaccine. We sought to replicate the associations discovered in that work by verifying these associations in a new cohort of 396 subjects, age 11–19 years (2nd cohort), all having had two doses of a rubella-containing vaccine. We found that B*2705 (median 1st cohort 20.9 IU/ml, p = 0.028; 2nd cohort 20.5 IU/ml, p = 0.001) and DPA1*0201 (median 1st cohort 32.5 IU/ml, p = 0.048; 2nd cohort 25.8 IU/ml, p = 0.025) alleles were consistently associated with lower rubella-induced antibodies. Further, DPB1*0401 (median 1st cohort 43.5 IU/ml, p = 0.021; 2nd cohort 36.2 IU/ml, p = 0.002) alleles were associated with higher antibody levels in both populations. The association of DRB1*04-DQB1*03-DPB1*03 (mean 1st cohort 25.2 IU/ml, p = 0.011; 2nd cohort 21.4 IU/ml, p = 0.032) and DRB1*15/16-DQB1*06-DPB1*03 (1st cohort 16.3 IU/ml, p = 0.043; 2nd cohort 19.1 IU/ml, p = 0.023) haplotypes with lower rubella-specific antibodies was observed in both studies. This study provides confirmatory evidence for an association between specific class I and II HLA markers and haplotypes with rubella vaccine-induced humoral responses and lends further weight to their influence on rubella immune responses.     

Impaired innate,humoral, and cellular immunity despite a take in smallpox vaccine recipients

Smallpox vaccine is highly effective, inducing protective immunity to smallpox and diseases caused by related orthopoxviruses. Smallpox vaccine efficacy was historically defined by the appearance of a lesion or “take” at the vaccine site, which leaves behind a characteristic scar. Both the take and scar are readily recognizable and were used during the eradication effort to indicate successful vaccination and to categorize individuals as “protected.” However, the development of a typical vaccine take may not equate to the successful development of a robust, protective immune response. In this report, we examined two large (>1000) cohorts of recipients of either Dryvax^® or ACAM2000 using a testing and replication study design and identified subgroups of individuals who had documented vaccine takes, but who failed to develop robust neutralizing antibody titers. Examination of these individuals revealed that they had suboptimal cellular immune responses as well. Further testing indicated these low responders had a diminished innate antiviral gene expression pattern (IFNA1, CXCL10, CXCL11, OASL) upon in vitro stimulation with vaccinia virus, perhaps indicative of a dysregulated innate response. Our results suggest that poor activation of innate antiviral pathways may result in suboptimal immune responses to the smallpox vaccine. These genes and pathways may serve as suitable targets for adjuvants in new attenuated smallpox vaccines and/or effective antiviral therapy targets against poxvirus infections.     

Needle-free delivery of influenza vaccine using the Med-Jet® H4 is efficient and elicits the same humoral and cellular responses as standard IM injection: A randomized trial

Background

Needle-free vaccine delivery systems have many potential advantages including increased vaccine compliance and decreased risk of needlestick injuries and syringe reuse. The Med-Jet® H4 is a gas-powered, auto-disabling disposable syringe jet injector. The Med-Jet family of products are currently being used in dermatology, podiatry, pain management and veterinary practices. The objectives of this study were to assess patient attitudes, time-efficiency, safety and immunogenicity of the seasonal influenza vaccine delivered by Med-Jet compared to the traditional needle-and-syringe.

2006-2015年武汉市风疹疫情流行病学分析

目的 了解2006-2015年武汉市风疹疫情的流行病学特征,为制定风疹免疫预防策略提供参考.方法 收集中国疾病预防控制信息系统中2006-2015年武汉市风疹个案病例疫情信息,采用描述流行病学方法分析风疹的流行病学特征.结果 2006-2015年累计报告风疹5 353例,2006-2008年报告发病率逐年上升,2009-2015年发病逐年下降,发病高峰为3～7月,发病前3位的地区为青山区、洪山区、武昌区.病例中男性多于女性(x2=156.40,P＜0.05),以学生为风疹的高发人群,发病年龄以10～19岁人群最多,占发病总数的69.33％.风疹病例中有风疹免疫史的占0.43％,武汉市适龄儿童含风疹成分疫苗接种剂次数逐年上升.结论 2006-2015年武汉市风疹报告发病呈波动下降趋势,但存在发病年龄后移现象,应做好适龄儿童2剂次含风疹成分疫苗的常规免疫外,尽快制定15岁以上人群的免疫预防策略.