Vaccine Update for Healthcare Providers

In the Journal - Archive

Paul A. Offit, MD, Director, Vaccine Education Center at The Children’s Hospital of Philadelphia

Contagious diseases in the U.S. from 1888 to the present

In November 2013, Donald Burke and coworkers at the University of Pittsburgh published an interesting study (van Panhuis WG, Grefenstette J, Jung SY, et al. Contagious Diseases in the United States from 1888 to the Present. N Engl J of Med. 2013 Nov 28;369(22):2152-8). The authors wanted to determine the impact of vaccines in the United States. Toward this end, they obtained weekly surveillance data published in the journal Morbidity and Mortality Weekly Report between 1888 and 2011. They used the year that a vaccine was licensed as the cutoff year to separate the pre-vaccine from post-vaccine period, realizing that uptake would be variable. They then multiplied the median weekly incidence rates from pre-vaccine years with population estimates for the post-vaccine years.

The authors estimated that about 103 million cases of disease had been prevented by vaccination since 1924. Of these hypothetical cases, about 26 million cases were prevented in the past decade. The disease with the most cases prevented was diphtheria (40 million cases), owing primarily to the fact that diphtheria had the second highest pre-vaccination incidence rate (237 cases per 100,000 population year) and the longest standing vaccine program. Second was measles (35 million cases), which had the highest disease incidence (318 cases per 100,000 population year).

Of interest, the disease with the most rapid decrease in the number of reported cases was measles (22 percent decrease each year post-vaccination). Rubella and polio were next, with annual decreases of 16 percent and 15 percent, respectively.

Perhaps more than any other, this study shows the incredible power and impact of America’s vaccine program.


Influenza-associated pediatric deaths

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.


Non-medical vaccine exemptions and pertussis in CA, 2010

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.


Vaccines and GBS

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.


Pregnancy dose Tdap and postpartum cocooning to prevent infant pertussis

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.


Vaccines and autism

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.


Vaccination Site and Risk of Local Reactions in Children 1 Through 6 Years of Age

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.


Egg-allergic patients can be safely vaccinated against influenza

Egg allergy is the second most common food allergy, affecting 1 percent to 2 percent of all children. In the United States, this corresponds to between 150,000 to 250,000 influenza-vaccine-eligible preschoolers. Anne Des Roches and coworkers at the Institutes of Health Research in Canada recently examined whether egg proteins contained in the influenza vaccine posed a real or only theoretical risk to patients with severe egg allergy (Des Roches A, et al., “Egg Allergic Patients Can Be Safely Vaccinated Against Influenza,” J Allergy Clin Immunol. 2012 Nov;130(5):1213-1216.

To answer this question, the authors conducted a prospective cohort study recruiting and vaccinating patients with egg allergy, including severe egg allergy (i.e., those with anaphylaxis or cardiorespiratory symptoms following egg ingestion). Patients were examined immediately before vaccination and remained under observation for 60 minutes post-vaccination. Over a span of five influenza seasons, 457 doses of trivalent inactivated influenza vaccine were administered to 367 patients among whom 132 had a history of severe egg allergy. None of the 367 patients developed anaphylaxis. The quantity of ovalbumin contained in these influenza vaccines ranged from 0.06 ug to 0.31 ug per dose (in other words, as much as 310 billionths of a gram of ovalbumin).

The authors also reviewed the medical literature, identifying an additional 4,172 egg-allergic patients in 26 studies who had safely received influenza vaccine (513 of those patients had severe egg allergies). The authors concluded that the quantity of egg protein contained in influenza vaccines is not sufficient to induce an anaphylactic response in patients known to have severe egg allergies, writing, “The risk of anaphylaxis appears sufficiently low for patients with egg allergy to be vaccinated like all other individuals without requiring administration by an allergist.”


Waning immunity with acellular pertussis vaccine

In October 2012, Nicola Klein and coworkers at the Kaiser Permanente Vaccine Study Center in Oakland, California, investigated the effectiveness of DTaP vaccine during a pertussis outbreak in California that had occurred in 2010 (Klein NP, Bartlett J, Rowhani-Rahbar A, et al., “Waning Protection after Fifth Dose of Acellular Pertussis Vaccine in Children,” N Engl J Med. 2012 Sep 13;367(11):1012-9.).

Investigators correlated the presence of pertussis illness as determined by pertussis-specific PCR with time following DTaP vaccine.They found that children who received DTaP between 4 and 6 years of age were at progressively greater risk in subsequent years. Specifically, the incidence of pertussis was 4.5 percent among 6-year-olds, 12.2 percent among 8-year-olds and18.5 percent among 10-year-olds. This increased incidence of pertussis between 6 and 10 years of age was followed by a sharp decrease in pertussis following the adolescent booster dose between 11 and 13 years of age.

The authors concluded that increased risk was associated with waning immunity following vaccination, not the natural history of pertussis infection. “The sharp increase in the incidence of pertussis among children 8 to 11 years of age, followed by a sharp decrease at 12 to 15 years of age, is not characteristic of the epidemiology of pertussis in unvaccinated persons or in previous outbreaks,” they wrote.

These data are consistent with previous studies in Canada and Australia showing that a switch from DTP to DTaP was associated with a decrease in protection against disease. Control of future outbreaks will likely require pertussis vaccines that evoke higher levels of protection and longer-lasting immunity.


Number and order of whole cell pertussis vaccines in infancy and disease protection

Similar to North America, Australia is in the midst of a pertussis epidemic. To understand the relative value in infants of DTwP (containing the whole-cell pertussis vaccine) vs. DTaP (containing the acellular pertussis vaccine), a group of investigators at Queensland Medical Research Institute and the University of Queensland in Brisbane, Australia, took advantage of a natural experiment (S. L. Sheridan, R. S. Ware, K. Grimwood, and S. B. Lambert, “Number and order of whole cell pertussis vaccines in infancy and disease protection,” JAMA 308 (2012): 454-456).

DTaP first became available in Queensland in 1996 and completely replaced DTwP by March, 1999. During that time, some children between 2 and 6 months of age received only DTwP and others only DTaP. For children born in 1998, investigators calculated the incidence of pertussis in children both before the current epidemic (1998-2008) and during the current epidemic (2009-2011). Investigators found that those who received only DTaP in infancy were 3.29 times more likely to develop pertussis than those who received only DTwP. Further, among those who received a mixture of DTaP and DTwP during infancy, those who received DTwP as their first dose were less likely to develop disease. This study confirms the observation in the United States that the DTaP vaccine is less effective than DTwP.

The decision to switch to an acellular pertussis vaccine was made because the whole-cell version was shown to have a fairly high rate of side effects, including persistent, inconsolable crying, fever, febrile seizures, and hypotonic-hyporesponsive syndrome. However, by switching to the acellular vaccine, which has a much more acceptable safety profile, we traded some efficacy for safety. Current outbreaks demonstrate just how big that trade was.


Benefits and limitations of the placebo response

In the July 14, 2011 issue of the New England Journal of Medicine, Michael Wechsler and co-workers from Harvard Medical School and Brigham and Women’s Hospital published a paper titled "Active or Placebo, Sham Acupuncture, or No Intervention in Asthma," (N Engl J Med. 2011 Jul 14;365(2):119-26). This is one of many papers showing the benefit of the placebo response — in this case, in the treatment of asthma.

Wechsler found that while a bronchodilator (albuterol) increased lung function by 20 percent, sham acupuncture and sham bronchodilators each increased lung function by 7 percent; no intervention had no effect. In other words, participants benefited from receiving something they thought might work. Of interest, although placebos have been shown to affect a variety of allergic and immunological diseases, study after study has shown that they don’t induce adaptive immune responses. The only way to get a viral- or bacterial-specific response is to be immunized or naturally infected. Although the placebo effect is a powerful one, it has its limits.


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