Vaccine Update for Healthcare Providers

In the Journal - Archive

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

• Egg-Allergic Patients Can Be Safely Vaccinated Against Influenza Nov. 2012
• Waning Immunity with Acellular Pertussis Vaccine Sept. 2012
• Number and Order of Whole Cell Pertussis Vaccines in Infancy and Disease Protection Aug. 2012
• Perfluorinated Compounds and Immune Response to Vaccines Feb. 2012
• The role of cost-effectiveness in U.S. vaccine policy Nov. 2011 
• “Near Elimination of Varicella Deaths in the US after Implementation of the Vaccination Program” Aug. 2011
• Benefits and limitations of the placebo response Jul. 2011

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.”

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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.

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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.

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Perfluorinated Compounds and Immune Response to Vaccines

On January 25, 2012, Philippe Grandjean and coworkers evaluated the relationship between perfluorinated compounds (PFCs) and immune response to vaccines in children living in the Faroe Islands (Grandjean P, Anderson EW, Budtz-Jorgensen E, et al. Serum vaccine antibody concentrations in children exposed to perfluorinated compounds. JAMA, 2012 Jan 25; 307(4): 391-7). PFCs are typically found in food packaging and textile impregnation and can contaminate food and drinking water. The authors correlated the quantity of various PFCs (such as perflurooctanoic acid and perfluorooctane sulfonic acid) to tetanus- and diphtheria-toxoid-specific immune responses. They found that higher levels of PFCs in blood correlated with a decreased capacity to respond to tetanus and diphtheria antigens; indeed, some toxoid-specific antibody levels were below those considered necessary for protection against disease (i.e., less than 0.1 IU/ml of antibody). 

This is the first paper reporting that PFCs cause a clinically significant decrease in vaccine-specific immune responses. It’s an extraordinary claim. Therefore, it should be backed by extraordinary evidence. This paper, unfortunately, provides less than extraordinary evidence for several reasons:

• The authors could have also examined immune responses to other vaccines that these children had been given (i.e., pertussis, Hib and polio), but chose not to. This was a lost opportunity and would have allowed the authors to support the robustness of their claim.
• The authors offer two previous studies — one in mice, the other in vitro — that supposedly support the biological plausibility of their assertion. However, the study in mice showed a suppression of IgM, not IgG responses and the study in vitro showed a decreased response to the mitogen LPS, neither of which is relevant to their findings of IgG-mediated, toxoid-specific responses in children.
• Because the study was not prospective, one worries that PFC exposure is a surrogate marker for something else, such as poorer nutrition. The authors controlled for PCB exposure, birth weight, maternal smoking during pregnancy and duration of breastfeeding, but this does not account for all other important confounders. In other words, the association between high PFC levels and low immune response to vaccines might not be causal.

In summary, this observation is interesting but needs to be reproduced by other investigators.

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The role of cost-effectiveness in U.S. vaccine policy

The November 10, 2011, issue of the New England Journal of Medicine contains an editorial by Jane Kim titled "The Role of Cost-Effectiveness in U. S. Vaccination Policy" (N Engl J Med. 2011 Nov 10;365(19):1760-1). Kim describes how health advisory bodies rarely consider cost-effectiveness when making recommendations about prevention and treatment. One notable exception, however, is the Advisory Committee for Immunization Practices (ACIP) to the Centers for Disease Control and Prevention (CDC), which routinely uses cost-effectiveness analyses to determine recommendations for new vaccines.

Kim focuses on two issues faced recently by the ACIP: The routine recommendation of Human Papillomavirus (HPV) vaccine for boys and conjugate meningococcal vaccines for infants. Kim doesn’t reach any specific conclusions, only to say that "identification of high value health interventions through comparative effectiveness analysis" is important. She tips her hand by stating that the public sector cost of fully vaccinating boys is currently $1,450 and for girls is $1,800, stating that this is "expensive" and "more than double the number in 1980." However, it would be of value to compare vaccines with other prevention modalities to determine where Americans are most likely to get bang for their healthcare buck. This is a much tougher analysis to make, but certainly worthwhile.

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“Near Elimination of Varicella Deaths in the US after Implementation of the Vaccination Program

On July 25, 2011, Mona Marin, John Zhang and Jane Seward from the CDC published a paper titled "Near Elimination of Varicella Deaths in the US After Implementation of the Vaccination Program" (Pediatrics. 2011 Aug;128(2):214-20).

The 1-dose varicella vaccine program was first implemented in the United States in 1995 with a second dose recommended in 2006. The authors examined the effect of a mostly 1-dose program by comparing the rates of varicella infection from 1990 to 1994 with those between 2005 and 2007. They found that the incidence of varicella declined from 0.41 per million in the population to 0.05 per million, an 88 percent decline. The decline was seen not only in those less than 20 years of age, but also in those less than 50, suggesting the impact of herd immunity. Further, in the six-year period between 2002 and 2007, three children were reported as having died from varicella as compared with 13 to 16 deaths reported per year in the pre-vaccine era.

The authors concluded, "The impressive decline in varicella deaths can be directly attributed to successful implementation of the 1-dose vaccination program. With the current 2-dose program, there is potential that these most severe outcomes of a vaccine-preventable disease could be eliminated."

Paul A. Offit, MD, offers comments on the latest research. Watch the video» (Medscape Infectious Diseases, August 2011)

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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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