Waning Of Immunity Research Articles

Progressive disseminated histoplasmosis in the HIV population in Europe in the HAART era. Case report and literature review

In highly endemic areas, up to 20 % of human immunodeficiency virus (HIV)-infected persons will develop progressive disseminated histoplasmosis (PDH). Europe is not endemic to histoplasmosis, and the disease is mainly found in immigrants often co-infected with HIV. We present a case of a patient with HIV and PDH highlighting the possible diagnostic difficulties that may arise in a non-endemic area and review the literature of histoplasmosis in the context of HIV infection with special focus on Europe. When cellular immunity wanes (usually at CD4 T-lymphocyte counts <150 cells/μL) histoplasma infection, acquired earlier, can reactivate and disseminate. PDH is an acquired immune deficiency syndrome(AIDS)-defining disease and a life-threatening infection, with a clinical spectrum ranging from an acute, fatal course with lung infiltrates and respiratory failure, shock, coagulopathy and multi-organ failure, to a more subacute disease with focal organ involvement, pancytopenia and hepatosplenomegaly. Mortality rates remain high for untreated patients, but early diagnosis, proper antifungal treatment and early initiation of antiretroviral therapy have improved the prognosis. European infectious diseases physicians, microbiologists and pathologists must be aware of histoplasmosis, particularly when facing HIV-infected immigrants from endemic areas. This is increasingly important due to migration and travel activities from these areas.

Mouse and Pig Models for Studies of Natural and Vaccine-Induced Immunity to Bordetella pertussis

The increasing incidence of whooping cough in many developed countries has been linked with waning immunity induced after immunization with acellular pertussis (aP) vaccines. The rational design of an improved aP vaccine requires a full understanding of the mechanism of protective immunity and preclinical studies in animal models. Infection of mice and pigs with Bordetella pertussis has many features of the infection seen in humans and has already provided valuable information on the roles of innate and adaptive immune responses in protection. Recent findings in these models have already indicated that it may be possible to develop an improved aP vaccine based on a formulation that includes a Toll-like receptor agonist as an adjuvant.

Duration of Protection After the First Dose of Acellular Pertussis Vaccine

Waning of pertussis immunity in older children prompted recommendations for a booster dose of acellular pertussis vaccine in pre-adolescence. Declining

Assessing Mumps Outbreak Risk in Highly Vaccinated Populations Using Spatial Seroprevalence Data

Mumps is a potentially severe viral infection. The incidence of mumps has declined dramatically in high-income countries since the introduction of mumps antigen-containing vaccines. However, recent large outbreaks of mumps in highly vaccinated populations suggest waning of vaccine-induced immunity and primary vaccine failure. In this paper we present a simple method for identifying geographic regions with high outbreak potential, demonstrated using 2006 mumps seroprevalence data from Belgium and Belgian vaccination coverage data. Predictions of the outbreak potential in terms of the effective reproduction number in future years signal an increased risk of new mumps outbreaks. Literature reviews on serological information for both primary vaccine failure and waning immunity provide essential information for our predictions. Tailor-made additional vaccination campaigns would be valuable for decreasing local pockets of susceptibility, thereby reducing the risk of future large-scale mumps outbreaks.

The Candidate TB Vaccine, MVA85A, Induces Highly Durable Th1 Responses

BackgroundVaccination against tuberculosis (TB) should provide long-term protective immunity against Mycobacterium tuberculosis (M.tb). The current TB vaccine, Bacille Calmette-Guerin (BCG), protects against disseminated childhood TB, but protection against lung TB in adolescents and adults is variable and mostly poor. One potential reason for the limited durability of protection may be waning of immunity through gradual attrition of BCG-induced T cells. We determined if a MVA85A viral-vector boost could enhance the durability of mycobacteria-specific T cell responses above those induced by BCG alone.MethodsWe describe a long-term follow-up study of persons previously vaccinated with MVA85A. We performed a medical history and clinical examination, a tuberculin skin test and measured vaccine-specific T cell responses in persons previously enrolled as adults, adolescents, children or infants into three different Phase II trials, between 2005 and 2011.ResultsOf 252 potential participants, 183 (72.6%) consented and completed the study visit. Vaccine-induced Ag85A-specific CD4+ T cell responses were remarkably persistent in healthy, HIV-uninfected adults, adolescents, children and infants, up to 6 years after MVA85A vaccination. Specific CD4+ T cells expressed surface markers consistent with either CD45RA−CCR7+ central memory or CD45RA−CCR7− effector memory T cells. Similarly durable Ag85A-specific CD4+ T cell responses were detected in HIV-infected persons who were on successful antiretroviral therapy when MVA85A was administered. By contrast, Ag85A-specific CD4+ T cell frequencies in untreated MVA85A-vaccinated HIV-infected persons were mostly undetectable 3–5 years after vaccination.ConclusionMVA85A induces remarkably durable T cell responses in immunocompetent persons. However, results from a recent phase IIb trial of MVA85A, conducted in infants from the same geographic area and study population, showed no vaccine efficacy, suggesting that these durable T cell responses do not enhance BCG-induced protection against TB in infants.

Age Related Differences in Dynamics of Specific Memory B Cell Populations after Clinical Pertussis Infection

For a better understanding of the maintenance of immune mechanisms to Bordetella pertussis (Bp) in relation to age, we investigated the dynamic range of specific B cell responses in various age-groups at different time points after a laboratory confirmed pertussis infection. Blood samples were obtained in a Dutch cross sectional observational study from symptomatic pertussis cases. Lymphocyte subpopulations were phenotyped by flowcytometry before and after culture. Memory B (Bmem) cells were differentiated into IgG antibody secreting cells (ASC) by polyclonal stimulation and detected by an ELISPOT assay specific for pertussis antigens pertussis toxin (Ptx), filamentous haemagglutinin (FHA) and pertactin (Prn). Bp antigen specific IgG concentrations in plasma were determined using multiplex technology. The majority of subjects having experienced a clinical pertussis episode demonstrated high levels of both Bp specific IgG and Bmem cell levels within the first 6 weeks after diagnosis. Significantly lower levels were observed thereafter. Waning of cellular and humoral immunity to maintenance levels occurred within 9 months after antigen encounter. Age was found to determine the maximum but not base-line frequencies of Bmem cell populations; higher levels of Bmem cells specific for Ptx and FHA were reached in adults and (pre-) elderly compared to under-fours and schoolchildren in the first 6 weeks after Bp exposure, whereas not in later phases. This age effect was less obvious for specific IgG levels. Nonetheless, subjects' levels of specific Bmem cells and specific IgG were weakly correlated. This is the first study to show that both age and closeness to last Bp encounter impacts the size of Bp specific Bmem cell and plasma IgG levels.

Mycoplasma pneumoniae Infections in Childhood

sible for up to 40% of community-acquired pneumonias in children over 5 years of age. Community-acquired pneumonias due to M. pneumoniae may increase several fold dur ing epidemics that occur every 4–7 years, believed to be due to waning of herd immunity and introduction of new subtypes into the population. the peak incidence reported in Scotland during the recent European epidemic was 14.2 per 100,000 population. 1 Milder presentations, typically tracheobronchitis, are at least 20 times more common than community-acquired pneumonias, and up to 20% of infections are asymptomatic. a recent Cochrane review concluded that diagnosis of infection based on clinical symptoms alone is not reliable. 2 therefore, accurate, rapid and cost-effective point of care diag

EPIDEMIOLOGICAL CONSEQUENCES OF IMPERFECT VACCINES FOR IMMUNIZING INFECTIONS.

The control of some childhood diseases has proven to be difficult even in countries that maintain high vaccination coverage. This may be due to the use of imperfect vaccines and there has been much discussion on the different modes by which vaccines might fail. To understand the epidemiological implications of some of these different modes, we performed a systematic analysis of a model based on the standard SIR equations with a vaccinated component that permits vaccine failure in degree ("leakiness"), take ("all-or-nothingness") and duration (waning of vaccine-derived immunity). The model was first considered as a system of ordinary differential equations, then extended to a system of partial differential equations to accommodate age structure. We derived analytic expressions for the steady states of the system and the final age distributions in the case of homogenous contact rates. The stability of these equilibria are determined by a threshold parameter Rp , a function of the vaccine failure parameters and the coverage p. The value of p for which Rp = 1 yields the critical vaccination ratio, a measure of herd immunity. Using this concept we can compare vaccines that confer the same level of herd immunity to the population but may fail at the individual level in different ways. For any fixed Rp > 1, the leaky model results in the highest prevalence of infection, while the all-or-nothing and waning models have the same steady state prevalence. The actual composition of a vaccine cannot be determined on the basis of steady state levels alone, however the distinctions can be made by looking at transient dynamics (such as after the onset of vaccination), the mean age of infection, the age distributions at steady state of the infected class, and the effect of age-specific contact rates.

Population-level effects of clinical immunity to malaria.

BackgroundDespite a resurgence in control efforts, malaria remains a serious public-health problem, causing millions of deaths each year. One factor that complicates malaria-control efforts is clinical immunity, the acquired immune response that protects individuals from symptoms despite the presence of parasites. Clinical immunity protects individuals against disease, but its effects at the population level are complex. It has been previously suggested that under certain circumstances, malaria is bistable: it can persist, if established, in areas where it would not be able to invade. This phenomenon has important implications for control: in areas where malaria is bistable, if malaria could be eliminated until immunity wanes, it would not be able to re-invade.MethodsHere, we formulate an analytically tractable, dynamical model of malaria transmission to explore the possibility that clinical immunity can lead to bistable malaria dynamics. We summarize what is known and unknown about the parameters underlying this simple model, and solve the model to find a criterion that determines under which conditions we expect bistability to occur.ResultsWe show that bistability can only occur when clinically immune individuals are more “effective” at transmitting malaria than naïve individuals are. We show how this “effectiveness” includes susceptibility, ability to transmit, and duration of infectiousness. We also show that the amount of extra effectiveness necessary depends on the ratio between the duration of infectiousness and the time scale at which immunity is lost. Thus, if the duration of immunity is long, even a small amount of extra transmission effectiveness by clinically immune individuals could lead to bistability.ConclusionsWe demonstrate a simple, plausible mechanism by which clinical immunity may be causing bistability in human malaria transmission. We suggest that simple summary parameters – in particular, the relative transmission effectiveness of clinically immune individuals and the time scale at which clinical immunity is lost – are key to determining where and whether bistability is happening. We hope these findings will guide future efforts to measure transmission parameters and to guide malaria control efforts.

Subnormal and waning immunity to tetanus toxoid in previously vaccinated HIV-infected children and response to booster doses of the vaccine

Little is known regarding waning immunity to tetanus toxoid (TT) in HIV-infected children and the need for booster doses before the recommended interval of 5-10 years. Anti-tetanus antibodies were assessed by ELISA in 24 HIV-infected and 24 control children. A protective level (>0.1 IU/ml) of TT antibodies was observed in 62% of HIV-infected children and in 100% of controls. HIV-infected children with five doses had a significantly (p=0.01) lower prevalence of protective immunity compared to controls. Follow-up anti-TT antibody levels in nine HIV-infected children declined from 1.27 to 0.26 IU/ml, but levels did not decline in the seven controls; five of the seven (71%) children with a non-protective level of antibodies responded with a level>0.16 IU/ml following one booster dose of the vaccine. HIV-infected children may need TT boosters before the recommended 5-10 years.

Effect of in-utero HIV exposure and antiretroviral treatment strategies on measles susceptibility and immunogenicity of measles vaccine

The high burden of maternal HIV-infection in sub-Saharan Africa may affect measles control. We evaluated the effect of in-utero HIV-exposure and antiretroviral treatment (ART) strategies on measles antibody kinetics prior and following measles vaccination. Infants aged 6-12 weeks were enrolled. This included HIV-uninfected infants born to HIV-uninfected (HUU) and HIV-infected mothers (HEU). Additionally, we enrolled perinatal HIV-infected infants with CD4% equal or greater than 25% randomized to deferred-ART until clinically or immunologically indicated (Group-3) or immediate-ART initiation (Group-4). Group-4 was further randomized to interrupt ART at 1 year (Group-4a) or 2 years of age (Group-4b). Additionally, a convenience sample of HIV-infected infants with CD4⁺ less than 25% initiated on immediate-ART was enrolled (Group-5). Measles immunoglobulin-G antibodies were quantified by an indirect enzyme immunoassay with titers 330 mIU/ml or more considered 'sero-protective'. The referent group was HUU-children. The proportion with sero-protective titers at 7.3 weeks of age was higher in HUU (65.2%) compared with any HIV-infected group (range: 16.7-41.8%), but dropped to less than 17% in all groups at age 19.6 weeks. Twenty-eight weeks following the first measles vaccine, Group-4a was less likely to have sero-protective titers (79.3%) as compared to HUU (91.1%; P<0.0001), Group-3 (95.7%; P=0.003) or Group-4b (92.1%; P=0.018). Although the proportion with sero-protective levels were similar between groups immediately postbooster dose, this was lower in HEU (79.6%; P=0.002) and Group-4a (80.3%; P=0.010) compared with HUU (94.3%) 41-weeks later. Greater waning of immunity among HIV-infected children in whom ART was interrupted and in HEU following a booster-dose, indicate the possible need for further measles-booster doses after 2 years of age in these children.

Committee Opinion No. 566

In the face of dramatic and persistent increases in pertussis disease in the United States, the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices has updated its guidelines for the use of the tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) for pregnant women. The new guidance was issued based on an imperative to minimize the significant burden of pertussis disease in vulnerable newborns, the reassuring safety data on the use of Tdap in adults, and the evolving immunogenicity data that demonstrate considerable waning of immunity after immunization. The revised Advisory Committee on Immunization Practices guidelines recommend that health care personnel administer a dose of Tdap during each pregnancy, irrespective of the patient's prior history of receiving Tdap. To maximize the maternal antibody response and passive antibody transfer and levels in the newborn, optimal timing for Tdap administration is between 27 weeks and 36 weeks of gestation, although Tdap may be given at any time during pregnancy. However, there may be compelling reasons to vaccinate earlier in pregnancy. There is no evidence of adverse fetal effects from vaccinating pregnant women with an inactivated virus or bacterial vaccines or toxoids, and a growing body of robust data demonstrates safety of such use. For women who previously have not received Tdap, if Tdap was not administered during pregnancy it should be administered immediately postpartum to the mother in order to reduce the risk of transmission to the newborn. Additionally, other family members and planned direct caregivers also should receive Tdap as previously recommended (sustained efforts at cocooning). Given the rapid evolution of data surrounding this topic, immunization guidelines are likely to change over time and the American College of Obstetricians and Gynecologists will continue to issue updates accordingly.

Successes and Shortcomings of Polio Eradication: A Transmission Modeling Analysis

Polio eradication is on the cusp of success, with only a few regions still maintaining transmission. Improving our understanding of why some regions have been successful and others have not will help with both global eradication of polio and development of more effective vaccination strategies for other pathogens. To examine the past 25 years of eradication efforts, we constructed a transmission model for wild poliovirus that incorporates waning immunity (which affects both infection risk and transmissibility of any resulting infection), age-mediated vaccination rates, and transmission of oral polio vaccine. The model produces results consistent with the 4 country categories defined by the Global Polio Eradication Program: elimination with no subsequent outbreaks; elimination with subsequent transient outbreaks; elimination with subsequent outbreaks and transmission detected for more than 12 months; and endemic polio transmission. Analysis of waning immunity rates and oral polio vaccine transmissibility reveals that higher waning immunity rates make eradication more difficult because of increasing numbers of infectious adults, and that higher oral polio vaccine transmission rates make eradication easier as adults become reimmunized. Given these dynamic properties, attention should be given to intervention strategies that complement childhood vaccination. For example, improvement in sanitation can reduce the reproduction number in problematic regions, and adult vaccination can lower adult transmission.

Determinants of Long-term Protection After Hepatitis B Vaccination in Infancy

The duration of protection after hepatitis B vaccination in early infancy is unclear and may be related to vaccination schedule, dosage, vaccine type and population characteristics. Factors potentially influencing waning immunity were assessed. A systematic review was performed. The main outcomes were prevalence of anti-hepatits B antibodies ≥ 10 mIU/mL after primary or booster vaccination. Factors potentially influencing protection were assessed in an adjusted random-effects meta-analysis model by age for both outcomes. Results of both meta-analyses were combined in a prognostic model. Forty-six studies reporting on the anti-hepatits B antibodies ≥ 10 mIU/mL 5 to 20 years after primary immunization and 29 on booster response were identified. The adjusted meta-analyses identified maternal carrier status (odds ratio [OR]: 2.37 [1.11; 5.08]), lower vaccine dosage than presently recommended (OR: 0.14 [0.06; 0.30]) and gap time between last and preceding dose of the primary vaccine series (OR: 0.44 [0.22; 0.86]) as determinants for persistence of anti-hepatits B antibodies ≥ 10. A lower vaccine dosage was also associated with failure to respond to booster (OR: 0.20 [0.10; 0.38]). The prognostic model predicted long-term protection of 90% [77%; 100%] at the age of 17 years for offspring of noncarrier mothers vaccinated with a presently recommended dose and vaccination schedule. Based on meta-analyses, predictors of waning immunity after hepatitis B vaccination in infancy could be identified. A prognostic model for long-term protection after hepatitis B vaccination in infancy was developed.

Effectiveness of Pentavalent and Monovalent Rotavirus Vaccines in Concurrent Use Among US Children &lt;5 Years of Age, 2009–2011

We assessed vaccine effectiveness (VE) for RotaTeq (RV5; 3 doses) and Rotarix (RV1; 2 doses) at reducing rotavirus acute gastroenteritis (AGE) inpatient and emergency department (ED) visits in US children. We enrolled children <5 years of age hospitalized or visiting the ED with AGE symptoms from November 2009-June 2010 and from November 2010-June 2011 at 7 medical institutions. Fecal specimens were tested for rotavirus by enzyme immunoassay and genotyped. Vaccination among laboratory-confirmed rotavirus cases was compared with rotavirus-negative AGE controls. Regression models calculated VE estimates for each vaccine, age, ethnicity, genotype, and clinical setting. RV5-specific analyses included 359 rotavirus cases and 1811 rotavirus-negative AGE controls. RV1-specific analyses included 60 rotavirus cases and 155 rotavirus-negative AGE controls. RV5 and RV1 were 84% (95% confidence interval [CI], 78%-88%) and 70% (95% CI, 39%-86%) effective, respectively, against rotavirus-associated ED visits and hospitalizations combined. By clinical setting, RV5 VE against ED and inpatient rotavirus-associated visits was 81% (95% CI, 70%-84%) and 86% (95% CI, 74%-91%), respectively. RV1 was 78% (95% CI, 46%-91%) effective against ED rotavirus disease; study power was insufficient to evaluate inpatient RV1 VE. No waning of immunity was evident during the first 4 years of life for RV5, nor during the first 2 years of life for RV1. RV5 provided genotype-specific protection against each of the predominant strains (G1P[8], G2P[4], G3P[8], G12P[8]), while RV1 VE was statistically significant for the most common genotype, G3P[8]. Both RV5 and RV1 significantly protected against medically attended rotavirus gastroenteritis in this real-world assessment.

Reduced Risk of Pertussis Among Persons Ever Vaccinated With Whole Cell Pertussis Vaccine Compared to Recipients of Acellular Pertussis Vaccines in a Large US Cohort

Unexpected waning of immunity after pertussis vaccination is now well described. In this study we examined whether prior vaccination with whole-cell pertussis vaccine (wP) at any point provided superior protection contrasted with a solely acellular pertussis vaccine (aP) series. We utilized the coincidence of a large outbreak of pertussis with the termination of wP availability, providing populations of children who had been vaccinated with combinations of wP and aP. Kaiser Permanente (KP) is an integrated healthcare system with complete electronic records and a centralized laboratory. Cases of laboratory-confirmed pertussis and vaccination data for members aged 8-20 years were retrieved. Among 263 496 persons aged 8-20 years, 904 cases of pertussis were identified. In patients with a full history of vaccinations administered by KP, those with 5 total doses of only aP had an 8.57 relative risk (RR) of pertussis (P < .0001) contrasted to those with ≥1 wP dose. With 6 doses of aP, the RR of disease was 3.55 (P < .0001). When external vaccine records were included, the results were similar. We found a markedly increased risk of disease associated with an entirely aP series. This risk was mitigated, but not eliminated, by the presence of a sixth dose of pertussis vaccine (Tdap). Receipt of 1 or more wP doses markedly augmented the durability of immunity from subsequent aP doses. It appears that a wholly acellular pertussis vaccine series is significantly less effective and durable than one that contains the traditional whole cell vaccine.

Pertussis resurgence: waning immunity and pathogen adaptation – two sides of the same coin

Pertussis or whooping cough has persisted and resurged in the face of vaccination and has become one of the most prevalent vaccine-preventable diseases in Western countries. The high circulation rate of Bordetella pertussis poses a threat to infants that have not been (completely) vaccinated and for whom pertussis is a severe, life-threatening, disease. The increase in pertussis is mainly found in age groups in which immunity has waned and this has resulted in the perception that waning immunity is the main or exclusive cause for the resurgence of pertussis. However, significant changes in B. pertussis populations have been observed after the introduction of vaccinations, suggesting a role for pathogen adaptation in the persistence and resurgence of pertussis. These changes include antigenic divergence with vaccine strains and increased production of pertussis toxin. Antigenic divergence will affect both memory recall and the efficacy of antibodies, while higher levels of pertussis toxin may increase suppression of the innate and acquired immune system. We propose these adaptations of B. pertussis have decreased the period in which pertussis vaccines are effective and thus enhanced the waning of immunity. We plead for a more integrated approach to the pertussis problem which includes the characteristics of the vaccines, the B. pertussis populations and the interaction between the two.

Pertussis: A Review of Disease Epidemiology Worldwide and in Italy

Pertussis continues to be a relevant public-health issue. The high coverage rates achieved have decreased the spread of the pathogen, but the waning of immunity implies a relevant role of adolescents and adults in the infective dynamics as they may represent a significant source of infection for unvaccinated or incompletely immunized newborns. The passive surveillance system is affected by many limitations. The underestimation of pertussis in adolescents, young adults and adults is mainly related to the atypical clinical characteristics of cases and the lack of lab confirmation. The real epidemiological impact of pertussis is not always perceived, anyway, the unavailability of comprehensive data should not hamper the adoption of active prophylactic interventions aimed at preventing the impact of waning immunity on pertussis. To avoid an increase of the mean age of acquisition of the infection, a booster dose of low-antigen content combined vaccine should be adopted in adolescents and adults. A decreased risk of infection in newborns can be achieved with the cocoon strategy, although the debate on this aspect is still open and enhanced surveillance and further studies are needed to fine-tune the pertussis prevention strategy.

Acellular Vaccines and Resurgence of Pertussis

PERTUSSIS IS A HIGHLY CONTAGIOUS, VACCINEpreventable disease for which a whole-cell vaccine (killed bacteria), in combination with toxoids against diphtheria and tetanus (DTwP), was introduced for immunization of children in the United States in the 1940s. With the eventual widespread use of DTwP vaccine, the national annual incidence of reported cases of pertussis decreased at least 150to 200-fold, with only 1010 reported cases in 1976. Because of high rates of both local and systemic adverse events associated with DTwP vaccine, acellular pertussis vaccines (DTaP) that contain a small number of purified antigens of Bordetella pertussis and have far fewer adverse effects replaced DTwP vaccine in the 1990s. The DTaP vaccine is currently recommended for both primary (3 doses administered at 2, 4, and 6 months of age) and booster (2 doses administered at 15 to 18 months and 4 to 6 years of age) immunizations. In 2005, formulations suitable for adolescents and adults (Tdap vaccine) were approved, and an additional 1-time booster dose is recommended. There has been substantial annual variation in the reported incidence of pertussis, even during the vaccine era, with epidemics every 2 to 5 years as the pool of susceptible individuals increases because immunity to pertussis, whether induced by immunization or by natural infection, is not longlasting. However, recently there has been an apparent resurgence of pertussis. In the United States, more than 25 000 and 27 000 cases were reported in 2005 and 2010, respectively, and there may be even more reported cases in 2012. Many more cases are undiagnosed and unreported. A report of the epidemiology of the 2010 epidemic of pertussis in California described more than 9000 cases and 10 deaths of infants as well as high rates of pertussis among preadolescents. In this issue of JAMA, Misegades and colleagues report results of a case-control study conducted to assess the role of unexpectedly rapid waning of immunity after the fifth dose of DTaP vaccine as an explanation for the unusually high incidence of pertussis, despite high rates of vaccination, among 7to 10-year-old children during the 2010 epidemic in California. The authors found that children with pertussis were less likely than controls to have received their fifth dose of DTaP within the prior 12 months, and the association increased with time after the fifth dose, from an odds ratio of 0.02 and estimated vaccine effectiveness of 98% in the first 12 months to an odds ratio of 0.29 and estimated vaccine effectiveness of 71% by 60 months or later. Since the age distribution of their 2016 controls was skewed toward younger ages compared with the ages of the cases, and to ensure that this age difference was due to waning immunity rather than a bias due to propensity to seek care, Misegades et al conducted additional analyses using 200 random samples of controls, assuming an even age distribution, and found little difference in the results. Two other case-control studies, using somewhat different methods, also concluded that there was substantial waning of immunity to pertussis among preadolescents during this epidemic. These studies, each from a single health care system, included fewer children with pertussis (277 and 171, respectively) than the study by Misegades et al, which included 682 cases with pertussis from 15 different counties and thus studied a more representative population. In addition, the study by Misegades et al was able to calculate an odds ratio for infection among fully vaccinated vs unvaccinated children (vaccine exemptors) and, from that, to validly estimate the vaccine’s effectiveness. In addition, a study conducted in Queensland, Australia, found that among children born in 1998 who had received various combinations of DTwP or DTaP vaccines for their 3-dose primary series, rates of pertussis during a large outbreak from 2009 to 2011 were substantially lower among children who had received either all doses or a first dose with DTwP compared with those who had received a first dose with DTaP. All of these are observational studies and cannot provide definitive evidence for causality. However, data from experimental studies on duration of effectiveness of acellular vaccines are unlikely to be available soon. Meanwhile, there is a growing consensus that acellular pertussis vaccines are less effective for controlling pertussis than the whole-cell

Report of epidemic pertussis in California

— Sarah S. Long, MD In this issue of The Journal, Winter et al, from the California Department of Health, report the 2010 statewide epidemic of pertussis totaling >9000 cases, 809 hospitalizations, and 10 deaths. Case numbers in 2010 exceeded those in any of the previous 60 years. Pertussis case burden is known to cycle every 3 to 5 years. Explanation for the extraordinary epidemic in California in 2010, despite steady immunization rates, is not known, but probably is multifactorial—including the addition of large birth cohorts of susceptible individuals, failure to immunize, and the availability of imperfect vaccines. The effectiveness of these vaccines soon after vaccination approaches only 90% and then begins to wane during the first 5 years after vaccination. One remarkable finding in California was the extraordinary incidence rates in Hispanic infants <6 months of age (588 per 100 000) compared with whites (<300 per 100 000), despite similar immunization rates. Another “new” epidemiologic feature of pertussis in California, which is beginning to become clear nationally, is the burden of disease in 10-year-old children compared with younger and older school-aged children. This presumably is due to their waning immunity since last receipt of DTaP before kindergarten entry, and their being a year shy of the 11-12year-old Tdap recommendation. In the accompanying editorial, Clark points out critical steps in pertussis outbreak control and focuses on research necessary to better understand the spread of infection and mechanisms of protection. Control of pertussis is as fragile as glass. Policy-making groups undoubtedly will look at data from the California outbreak, as well as national data, to determine whether a change in immunization policy could be beneficial or might risk further cracks in the glass. Meanwhile, because all 10 deaths in the California outbreak occurred in infants <3 months of age, the current recommendations Centers for Disease Control and Prevention and the American Academy of Pediatrics to immunize pregnant women with Tdap after 20 weeks of gestation must be implemented urgently, as should pertussis vaccine recommendations for all other age groups, which now includes a single dose of Tdap for all persons from 11 years of age through the elderly. Article page 1091< Editorial page 980<