Paul A. Offit, MD, Director, Vaccine Education Center at The Children’s Hospital of Philadelphia
In the November 2013, Karen Wong and coworkers from the Centers for Disease Control and Prevention (CDC) published a study about influenza-associated deaths among children (Wong KK, Jain S, Blanton L, et al, “Influenza-Associated Pediatric Deaths in the United States, 2004-2012,” Pediatrics 2013 Nov;132(5):796-804.). The authors made several interesting observations:
This study underlines the importance of immunizing all children older than 6 months of age, independent of whether they have a medical condition that puts them at greater risk of fatal influenza infection.
During the past few years, several studies have shown that immunity to the acellular pertussis vaccine (DTaP and Tdap) fades more quickly than that found following the whole cell pertussis vaccine (DTP). The lesser effectiveness of the acellular vaccine has been in part responsible for the current outbreaks of pertussis throughout the United States. One could then reasonably ask to what extent, if any, do children whose parents have chosen not to immunize them contribute to the current outbreaks.
To answer this question, Jessica Atwell and coworkers studied a recent pertussis outbreak (Atwell JE, Van Otterloo J, Zipprich J, et al. “Non-medical vaccine exemptions and pertussis in California, 2010,” Pediatrics. 2013 Oct;132(4):624-630). The authors investigated an outbreak in 2010 that affected 9,120 people, the largest pertussis outbreak in California since 1947. This wasn’t an easy study to do — many factors contribute to pertussis outbreaks. In addition to waning immunity, other factors include better diagnosis, increased awareness, and the cyclical nature of the disease.
The authors found 39 clusters of children whose parents had chosen not to vaccinate them for non-medical (philosophical or religious) reasons. They found that more cases of pertussis occurred in and around these clusters of non-medical exemptions than in areas that didn’t have these clusters. In other words, waning immunity was not the only, or arguably most significant, factor in determining whether children would get pertussis. This article is one more argument for the importance of pertussis vaccine in the face of continuing outbreaks.
In September 2013, Chris Stockmann and coworkers at the University of Utah Health Sciences Center in Salt Lake City reported the incidence and clinical characteristics of children admitted with pneumococcal meningitis (Stockmann C, Ampofo K, Byington CL, et al. Pneumococcal Meningitis in Children: Epidemiology, Serotypes, and Outcomes from 1997-2010 in Utah. Pediatrics. 2013 Sep;132(3):421-8).
The conjugate pneumococcal vaccine containing 7 serotypes (PCV7) was licensed and recommended for universal use in infants in the United States in 2000. In Utah, the incidence of pneumococcal meningitis in children less than 2 years of age decreased by 52 percent between 1996 and 2000 (before licensure) and 2006 and 2009 (after licensure).
The authors of this study identified 68 cases of meningitis between 1997 and 2010. They found that PCV7 serotypes accounted for 64 percent of cases before licensure of PCV7 vaccine and 25 percent of cases after licensure. The case fatality rate was similar for PCV7 and non-PCV7 serotypes. Among the survivors, 63 percent had neurological sequelae including seizures, developmental delay, and sensorineural hearing loss requiring cochlear implants. Most strikingly, about 54 percent of children infected with PCV7 serotypes had been unimmunized.
Pneumococcal meningitis is a serious and occasionally fatal disease with a high incidence of permanent sequelae. The importance of immunization in protecting against this disease cannot be overemphasized.
On August 2, 2013, the Centers for Disease Control and Prevention (CDC) published results of vaccine coverage rates among kindergarteners in the United States (“Vaccination Coverage Among Children in Kindergarten—United States, 2012-2013 School Year,” Morbidity and Mortality Weekly Report (2013): 62: 607-613).
There was good news and bad news.
First: the good news. Forty-eight states and the District of Columbia reported vaccination coverage rates with medians of 94.5% for 2 doses of measles, mumps, and rubella (MMR) vaccine; 95.1% for 4 doses of diphtheria, tetanus, and acellular pertussis (DTaP) vaccine; and 93.8% for 2 doses of varicella vaccine. These rates are at or near the national Healthy People 2020 targets of maintaining 95% vaccination coverage for each of these vaccines.
Now: the bad news. Non-medical exemptions to vaccination are becoming a growing problem. All states allow medical exemptions; 46 allow religious exemptions; and 18 allow philosophical exemptions. Only two states, Mississippi and West Virginia, don’t allow either religious or philosophical exemptions. The overall rate of non-medical exemptions was 1.8%. Four states, however, have levels of non-medical exemptions that exceed 5%. Oregon had the highest rate at 6.4%, followed by Vermont (5.7%), Idaho (5.5%), and Michigan (5.3%). (The state with the lowest level of non-medical exemptions was New Mexico at 0.2%). Because low vaccination rates and high exemption rates often cluster in communities, these states are at the highest risk of outbreaks caused by vaccine-preventable illnesses.
This information should be a warning bell for health departments to develop evidence-based communications strategies to protect kindergarteners from harm caused by vaccine-preventable illnesses, especially those in states at highest risk.
In 1976, fear of an impending influenza pandemic caused public health officials to launch a vaccine program that eventually included 40 million Americans. The vaccine virus used, an H1N1 strain colloquially referred to as “swine flu” vaccine, was found in retrospective studies to be a rare cause of Guillain-Barré Syndrome (GBS), a disease characterized by ascending paralysis. Approximately, 1 of every 100,000 people inoculated with the pandemic influenza vaccine developed GBS. This unfortunate association opened the door to the notion that other influenza vaccines — or indeed any vaccine — could cause GBS.
In response to public concern about the association of vaccines and GBS, Roger Baxter and colleagues at the Kaiser Permanente Vaccine Study Center examined the relationship between vaccines and GBS in 415 patients hospitalized with the disease in Northern California between 1995 and 2006 (Baxter R, Bakshi N, Fireman B, et al. Lack of Association of Guillain-Barré Syndrome With Vaccinations. Clinical Infect Dis. 2013 Jul;57(2):197-204). The authors found that the likelihood of receiving influenza vaccine six weeks prior to the onset of GBS was indistinguishable from the likelihood of receiving the vaccine within the previous nine months. In other words, people with GBS were not more likely to have received influenza vaccine recently than they were to have received the vaccine in the distant past. The same was true for tetanus vaccine, the 23-valent pneumococcal vaccine, and for all three vaccines combined.
The authors concluded, “In this large retrospective study, we did not find evidence of an increased risk of GBS following vaccinations of any kind, including influenza vaccination.” These findings should be reassuring to patients and parents who have been particularly worried about this association.
On May 27, 2013, Andrew Terranella and colleagues from the Centers for Disease Control and Prevention (CDC) studied the efficacy and cost effectiveness of two different strategies to prevent pertussis in infants: 1) immunizing pregnant women with Tdap between 27 and 36 weeks’ gestation, and 2) “cocooning,” which means immunizing mothers and family contacts after the baby has been delivered. This study is important because virtually all deaths from pertussis occur in infants less than 3 months of age. Therefore, pertussis deaths are occurring in those too young to be protected by active vaccination.
The authors found that immunization with Tdap during pregnancy was the preferred strategy. Pregnancy vaccination was better than cocooning for preventing pertussis cases (33 percent vs. 20 percent), pertussis hospitalizations (38 percent vs. 19 percent), and pertussis deaths (49 percent vs. 16 percent). Further, the cost per quality-adjusted life-year saved was substantially less for pregnancy vaccination ($414,000 vs. $1, 173,000).
These results are consistent with the biology of the situation. Babies are better off being protected by circulating antibodies passively acquired from mothers immunized during pregnancy than by counting on all those around them to be immunized.
Terranella A, Asay GR, Messonnier ML, Clark TA, Liang JL. Pregnancy Dose Tdap and Postpartum Cocooning to Prevent Infant Pertussis: A Decision Analysis. Pediatrics. 2013 Jun;131(6):e1748-56.
In May 2013, Roger Baxter and coworkers reported the long-term effectiveness of varicella vaccine (Baxter R, Ray P, Tran TN, et al. Long-term effectiveness of varicella vaccine: a 14-year, prospective cohort study. Pediatrics 2013 May;131(5):e1389-96). In 1995, the varicella vaccine was first licensed and recommended for universal use in the United States in children 12 months of age or older. In 2006, a second dose of varicella vaccine was recommended for children 4 to 6 years of age.
The authors followed 7,585 children vaccinated in 1995 through 2009. A total of 2,826 of these children also received a second dose of varicella vaccine between 2006 and 2009. Rates of varicella and herpes zoster were determined in these children and compared with rates of disease prior to the introduction of vaccine.
The authors found that the incidence of varicella was 15.9 per 1,000 person years, about ten-fold lower than in the pre-vaccine era. Vaccine effectiveness at the end of the study period was still 90 percent without evidence of waning immunity over time. Most cases of disease in vaccinated children were mild and occurred early after vaccination. No child developed varicella after a second dose. Similarly, rates of herpes zoster infections were lower in vaccinated children than had been observed in the pre-vaccine era, suggesting that varicella vaccine reduces the incidence of shingles.
The authors concluded that one dose of varicella vaccine provided excellent protection against moderate to severe disease, that immunity to the virus did not appear to fade during the 14-year follow-up period and that varicella vaccine might reduce the incidence of zoster as children get older.
In a paper published in March 2013, Frank DeStefano and colleagues addressed the relationship between vaccines and autism (DeStefano F, Price CS , Weintraub, ES. Increasing Exposure to Antibody-Stimulating Proteins and Polysaccharides in Vaccines Is Not Associated with Risk of Autism. J Pediatr. 2013 Mar 29. doi 10.1016/j.jpeds.2013.02.001).
Three hypotheses have evolved during the past 15 years. In 1998, Andrew Wakefield and coworkers claimed that the combination measles-mumps-rubella (MMR) vaccine caused autism: a contention now refuted by 12 well-controlled studies. One year later, concern shifted to thimerosal, an ethylmercury containing preservative used in several vaccines given to infants. Seven studies have now clearly refuted the thimerosal-causes-autism hypothesis. More recently, concern about vaccines and autism settled on the fear that children were receiving too many vaccines too soon.
The first paper to address this issue showed no relationship between the number of vaccines received in the first year of life and the development of autism (Smith MJ, Woods CR. On-time vaccine receipt in the first year does not adversely affect neuropsychological outcomes. Pediatrics. 2010 Jun;125(6):1134-41). The study by DeStefano advances the findings of the previous study in that it looks not only at the number of vaccines received but at the number of immunological components contained in those vaccines. DeStefano and coworkers examined the quantity of antigens received by 250 children with autism spectrum disorder (ASD) and 750 children without ASD. They found no relationship between antigenic burden from vaccines and autism.
Taken together, these studies should reassure concerned parents that although the cause or causes of autism remain unclear, one thing that has become clear is that vaccines aren’t to blame.
In February 2013, investigators at Vanderbilt University in collaboration with the Centers for Disease Control and Prevention (CDC) evaluated the efficacy of influenza vaccine at preventing hospitalizations caused by influenza virus in adults (Talbot HK, Zhu Y, Chen Q, Williams JV, Thompson MG, Griffin MR. Effectiveness of influenza vaccine for preventing laboratory-confirmed influenza hospitalizations in adults, 2011-2012 influenza season. Clin Infect Dis. 2013 Feb 28.). Investigators evaluated adults admitted with acute respiratory disease to one academic and three community hospitals in the Nashville, Tennessee area. Eligibility criteria included an admission diagnosis of pneumonia, influenza, or acute respiratory disease plus at least two of the following: temperature greater than 100oF or less than 96.8oF, new onset of cough, dyspnea, chills, headache, myalgia or sore throat. Patients with symptoms lasting longer than 10 days or having been treated with antivirals were excluded. Diagnosis of influenza virus infection was made by reverse-transcriptase polymerase chain reaction (RT-PCR). Of 191 eligible patients, 21 had confirmed influenza.
The Vanderbilt investigators found that influenza vaccine effectiveness was 71.4 percent for all adults and 76.8 percent for adults 50 years of age and older. These results stand in contrast to results of vaccine efficacy recently published by the CDC (CDC, “Interim adjusted estimates of seasonal influenza vaccine effectiveness—United States, February 2013,” Morbidity and Mortality Weekly Report (2013) 62:119-123). According to CDC data, vaccine effectiveness was 56 percent overall with the following breakdown by age: 58 percent for 6 month to 17-year-olds; 46 percent for 18- to 49-year-olds; 50 percent for 50- to 64-year-olds, and 9 percent for those 65 years of age and older. However, CDC data were based on protection against outpatient visits whereas the Vanderbilt data were based on protection against hospitalization. According to these two sets of data, influenza vaccine is better at preventing more severe disease.
Although the influenza vaccine is imperfect, it remains to best tool we have to prevent severe and occasionally fatal influenza virus infections.
On February 7, 2013, the New England Journal of Medicine published an article titled, “Pertactin-Negative Variants of Bordetella pertussis in the United States” (Queenan AM, Cassiday PK, Evangelista A. N Engl J Med. 2013 Feb 7;368(6):583-4). In this report, researchers at St. Christopher’s Hospital for Children in Philadelphia examined 12 isolates of B. pertussis obtained from children admitted to their hospital. They found that 11 of the 12 isolates no longer contained pertactin, a structural protein associated with bacterial virulence. Two of the three DTaP vaccines used in the United States (ACEL-IMUNE® and Infanrix®) contain pertactin. Also, both Tdap vaccines, Boostrix® and Adacel®, contain pertactin. It is possible that these pertactin-negative isolates are the result of selective pressure exerted by widespread vaccination with pertactin-containing vaccines.
The more important question, however, is what does this mean. The authors concluded, “Although much attention has been given to the waning immunity associated with the introduction of acellular vaccines, another factor contributing to the outbreaks may be the adaptation of B. pertussis to vaccine selection pressure.” To date, however, pertactin-negative isolates are a microbiological finding in search of clinical relevance. First, pertactin-negative strains, which have been isolated in Japan, France and Finland, have not been shown to be at the center of outbreaks in those countries. Second, pertactin-negative strains have not been found to be associated with outbreaks in the United States. Therefore, there remains no evidence to support the concern that pertussis outbreaks in the United States or elsewhere are associated with anything other than waning immunity caused by acellular vaccines, which are clearly less effective albeit safer than the whole-cell vaccines.
It would have been of value to have had data that pertactin-negative strains were clinically relevant before publication. Otherwise, the media will latch on to this finding as potentially important without evidence to suggest that it as anything other than a curiosity.
In February 2013, Lisa Jackson and coworkers, working with data from the Vaccine Safety Datalink, published a study examining local site reactions following intramuscular (IM) injections of the hepatitis A, influenza, and diphtheria-tetanus-acellular pertussis (DTaP) vaccines (Jackson L ., Peterson D, Nelson JC, et al. “Vaccination Site and Risk of Local Reactions in Children 1 Through 6 Years of Age,” Pediatrics 2013 Jan 14; 131:283-289). The authors wanted to know whether children were more likely to develop local injection site reactions if they were inoculated in the arms as compared with their thighs. The Advisory Committee on Immunization Practices (ACIP) currently recommends that IM immunizations be administered in the arm muscle (deltoid) for children 3 years of age and older and in the anterolateral thigh muscle (quadriceps) for toddlers 12 through 35 months of age.
The authors performed a retrospective, cohort study of 1.4 million children who received 6 million IM vaccines between 2002 and 2009. They found that local reactions were greater after IM inoculation of DTaP in the arm than in the leg in children 12 to 35 months of age and in children 3 to 6 years of age; however, the difference in the older group was not statistically significant. Injection site reactions following both influenza and hepatitis A vaccines were uncommon, and there were no differences between arm and leg inoculation.
These data support the ACIP recommendation for IM inoculations in the thighs of younger children.
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