Vaccine Update for Healthcare Providers

In the Journals

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

California pertussis epidemic, 2010

In December 2012, Kathleen Winter and coworkers from the California Department of Public Health in Sacramento reported the details of a pertussis outbreak in 2010 (Winter K, et al. California Pertussis Epidemic, 2010, J Pediatr. 2012 Dec;161(6):1091-6. Investigators made several observations of interest:

  1. Nine (9) percent of children sickened by pertussis were unvaccinated.
  2. High disease rates were observed in fully vaccinated 10-year-olds, suggesting a waning of immunity prior to the adolescent booster dose.
  3. Ten fatal cases were reported, all were younger than 2 months of age.

As of late October 2012, about 36,000 cases of pertussis had been reported in the United States; associated with 16 deaths. As was the case in California, all the deaths occurred in children younger than 2 months old — an age too young to benefit from active immunization. For this reason, the Advisory Committee for Immunization Practices to the Centers for Disease Control and Prevention (CDC) recently recommended that all pregnant women be vaccinated with Tdap during either the late second or third trimester of pregnancy, and that they receive Tdap during all subsequent pregnancies. If followed, this recommendation should decrease the number of deaths from pertussis by allowing newborns to receive passively transferred pertussis-specific antibodies through the placenta prior to birth.

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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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HPV vaccine and promiscuity

In October 2012, Robert Bednarczyk and coworkers at Kaiser Permanente, the Rollins School of Public Health, and Emory University in Atlanta, Georgia, performed a study to determine whether receipt of HPV vaccine among adolescents led to an increase in sexual activity (Bednarczyk RA, Davis R, Ault K, Orenstein W, and Omer SB. Sexual Activity-Related Outcomes After Human Papillomavirus Vaccination of 11- to 12-Year-Olds. Pediatrics, 2012; 130:798-805).

To answer this question, they enrolled 1,398 girls; 493 had received the vaccine and 905 hadn’t. To determine the level of sexual activity following vaccination, investigators examined medical records for the incidence of pregnancy, the number of tests ordered or diagnoses made for sexually transmitted diseases, and the number of adolescents who had sought contraceptive counseling. They found no differences in these two groups among any of the outcome measures, concluding, “HPV vaccination in the recommended ages was not associated with increased sexual activity-related outcomes.”

The fear that HPV vaccination would increase sexual promiscuity was never well founded. First: HPV vaccine doesn’t protect against other sexually transmitted diseases such as gonorrhea, syphilis or chlamydia. Second: HPV vaccine doesn’t protect against all serotypes of HPV. Third: no vaccine, including the HPV vaccine, is 100 percent effective. Frankly, the notion that HPV vaccine would increase sexual activity is analogous to the notion that receipt of a tetanus vaccine would cause an increase in people feeling more comfortable stepping on a bed of rusty nails.

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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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Herd immunity and the HPV vaccine

In 2006, the CDC recommended the quadrivalent human papillomavirus (HPV) vaccine for adolescent women in the United States. Several post-licensure studies have evaluated the safety of the vaccine among large groups. However, no study had previously evaluated the impact of the vaccine on acquisition of HPV in the community. In July 2012, Jessica Kahn and coworkers evaluated a group of women to determine not only the efficacy of the vaccine against vaccine serotypes, but also the presence of herd immunity (Kahn JA, Brown DR, Ding L, et al. “Vaccine-Type Human Papillomavirus and Evidence of Herd Protection After Vaccine Introduction,” Pediatrics 2012 Jul 9.) See also “In the Media” section.

Researchers studied a group of mostly African American women in the Cincinnati, Ohio, area who either did or did not receive HPV vaccine. Immunization rates were about 59 percent — somewhat higher than the national average of about 42 percent. Not surprisingly, investigators found a decrease in the prevalence of HPV infections after introduction of vaccine compared with before the introduction of vaccine. This decrease in vaccine prevalence occurred not only in the vaccinated group (32 percent versus 10 percent), but also in the unvaccinated group (30 percent versus 15 percent). In other words, there was clear evidence for herd immunity. Although models have been postulated that predict the degree of herd immunity likely to occur following introduction of various vaccines (see P. Fine, “Community Immunity,” In Vaccines, Plotkin SA,Orenstein WA, Offit PA, editors. Vaccines, 5th ed. Elsevier, 2008), the real proof occurs only after vaccines have been introduced. It’s encouraging that herd immunity was seen in this cohort; but it should be kept in mind that immunization rates among this group of young women were higher than that in the general population.

Typically, herd immunity for highly contagious diseases isn’t observed until immunization rates are quite high. However, after introduction of the bovine-human reassortanat rotavirus vaccine, RotaTeq®, in 2006, herd immunity was observed fairly quickly for this highly contagious infection. Within a few years, although only 50 percent of young infants had been vaccinated, an 80 percent reduction in disease was observed, arguing that the vaccine had significantly reduced the quantity of wild-type virus shed in the community. When Jonas Salk’s inactivated polio vaccine was introduced in 1955, herd immunity was observed within a few years associated with immunization rates of only 40 percent. It will be interesting to see whether the findings of Kahn and coworkers are reproduced in different settings among different populations of young women and men.

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Alternative immunization schedules

On June 18, 2012, researchers from the Oregon Immunization Program and the Centers for Disease Control and Prevention (CDC) published a paper titled “Frequency of Alternative Immunization Schedule Use in a Metropolitan Area” (Robison SG, Groom H, and Young C. Pediatrics 2012;130:32-38). The purpose of the study was to evaluate the percentage of parents who chose to delay or withhold vaccines. What they found was troubling. Between 2006 and 2009, the percentage of parents in Oregon choosing an “alternative” vaccine schedule increased from 2.5 percent to 9.5 percent. Children whose parents chose this schedule received fewer shots per visit but visited the physician more frequently for their immunizations.

With increasing outbreaks of measles and pertussis in the United States, the results of this study shouldn’t be surprising. What is surprising is the general acceptance of the phrase “alternative immunization schedule.” In truth, there is no alternative vaccine schedule. There is only the schedule recommended by the CDC and AAP — a schedule that has been rigorously and thoroughly tested. Neither the CDC nor AAP recommend an alternative. We should call the “alternative schedule” what it is, a delayed vaccine schedule without benefit but with the very real possibility of doing harm.

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Adults aren’t aware of Tdap vaccine

In May 2012, Beth Halperin and coworkers from Dalhousie University in Halifax, Nova Scotia reported the results of a web-based survey of more than 4,000 people 18 years of age or older. Results were presented at the 15th Annual Conference on Vaccine Research, Session 57, at the National Foundation for Infectious Diseases meeting in Baltimore, Maryland. Halperin was interested in determining the level of education among participants about the pertussis vaccine. Like the Advisory Committee for Immunization Practices, Canada’s National Advisory Committee on Immunization recommends a single dose of Tdap for all adults. The report is timely because increasing numbers of cases of pertussis have been reported in the U. S. since 2006. It is now estimated that between1-2 million Americans suffer from pertussis every year.

Investigators found that:

On the bright side, information gleaned from focus groups surveyed by these investigators showed that most people were open to learning about vaccines from healthcare providers. “It’s not that they don’t want to know,” said Halperin. “It’s that they don’t have the information.”

More information about porcine circovirus (PCV) in rotavirus vaccines

On January 5, 2012, investigators from Merck Research Laboratories published a study evaluating the level of contamination of the bovine-human reassortant rotavirus vaccine (RotaTeq®) with porcine circovirus (PCV) (Ranucci CS, Tagmyer T, Duncan P. “Adventitious Agent Risk Assessment Case Study: Evaluation of RotaTeq® for the Presence of Porcine Circovirus.” PDA J Pharm Sci Technol. 2011 Nov 1;65(6):589-98). This was an issue when contamination with PCV was found in both RotaTeq and Rotarix® a few years after RotaTeq had been licensed. Although PCV had not been shown to cause disease in humans, the finding of contamination was concerning. This study provides additional evidence that the small quantities of residual PCV DNA found in RotaTeq were not clinically important.

Investigators found that bulk lots of RotaTeq:

  1. Did not contain DNA fragments of PCV-1
  2. Did contain low levels of DNA fragments of PCV-2
  3. Did not contain infectious PCV-1 or PCV-2

The source of PCV-2 DNA was the gamma-irradiated porcine trypsin that had been used to facilitate vaccine virus growth. Most importantly, the vaccine did not induce PCV-2-specific antibodies in vaccinees. These data confirm the fact that RotaTeq did not contain live PCV-2, inactivated whole PCV-2, or even sufficient quantities of PCV-2 proteins to induce an immune response. Similarly, large, prospective well-controlled studies of this vaccine showed that it did not induce symptoms that would suggest contamination with another virus.

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UK Parents’ Decision-Making About Measles-Mumps-Rubella (MMR) Vaccine 10 Years After the MMR-Autism Controversy: A Qualitative Analysis

Recently, Katrina Brown and colleagues from the Center for Patient Safety and Service Quality at the Imperial College of London, as well as several other health agencies, investigated parents’ attitudes and beliefs about the measles-mumps-rubella (MMR) vaccine (Brown KF, Long SJ, Ramsay M, et al., “UK Parents’ Decision-Making About Measles-Mumps-Rubella (MMR) Vaccine 10 Years After the MMR-Autism Controversy: A Qualitative Analysis,” Vaccine. 2012 Feb 27;30(10):1855-64). The authors interviewed 24 mothers about their decision to give or not give MMR vaccine to their children now that the controversy is more than a decade old.

Several of their findings were not intuitive. First, investigators found that independent of whether they had chosen to give MMR, mothers were generally sympathetic to Andrew Wakefield, perhaps as a result of the lengthy trial that ended in his being struck off the medical register. Second, those who chose not to give MMR were not concerned about immunological overload because three vaccines were contained in a single shot; rather, they had a vague notion that something was intrinsically unsafe about the vaccine itself, although they often couldn’t pinpoint what it was. Third, parents who chose not to vaccinate criticized other parents for not being open-minded to their choice, arguing that they felt pressured to vaccinate. This tension might reflect a shift toward a choice not to get vaccinated as socially unacceptable.

It is unclear to what extent these findings among mothers in London are relevant to the United States. For example, while thimerosal was a major concern in the U.S., it wasn’t a concern in England. Conversely, the MMR controversy had a much bigger impact in England than the U.S. Also, conclusions from this study were qualitative and based on a small number of parents.

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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:

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

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Hospitalizations for intussusception before and after the reintroduction of rotavirus vaccine in the United States

On January 2, 2012, a group of investigators from the University of Michigan published their findings from an evaluation of the impact of the routinely recommended rotavirus vaccine on the incidence of intussusception in the United States (Zickafoose SJ, Benneyworth BD, Riebschleger MP, et al. “Hospitalizations for Intussusception Before and After the Reintroduction of Rotavirus Vaccine in the United States,” Arch Pediatr Adolesc Med. 2012 Jan 2.). They wanted to see whether there was any change in the incidence of hospital discharges for intussusception in children less than 1 year of age in several years before vaccination (1997, 2000, 2003, and 2006) and three years after vaccination (2009).

This study is best understood by reviewing the history of rotavirus vaccines. In 1998, the rhesus-human reassortant rotavirus vaccine (RotaShield®) vaccine was introduced and routinely recommended for all infants. Within one year of its introduction, the vaccine was found to be a rare cause of intussusception (1 case of intussusception in roughly 10,000 vaccinees). As a consequence, it was withdrawn from use. Seven years passed. The next rotavirus vaccine, a series of bovine-human reassortant rotaviruses (RotaTeq®), was introduced in 2006 and a third rotavirus vaccine, an attenuated human (RotaRix®) strain, was introduced in 2008.

Because no one really knew why RotaShield caused intussusception, no one knew whether the two new vaccines would also cause it. As it turned out, from studies in Australia, Brazil and Mexico, both new vaccines were also found to be rare causes of intussusception. This time, however, the incidence was about 1 in 60,000 to 90,000 vaccinees instead of 1 in 10,000. Because all three rotavirus vaccines were rare causes of intussusception, researchers now questioned whether natural rotavirus infection is also a rare cause of intussusception.

So, the question became which is more rare: intussusception after natural infection or intussusception after vaccination? If rotavirus vaccines cause intussusception more commonly than natural infection, then the rate of intussusception should go up in a highly vaccinated population. If natural infection is a more common cause of intussusception then the rate of intussusception should go down in a highly vaccinated population (because the vaccine prevents natural infection).

The study by Zickfoose and coworkers found no change in the incidence of intussusception in the United States before or after introduction of the vaccine. These findings suggest that both vaccine-induced and disease-induced intussusception occur at the same rate. More studies are needed to confirm this result.

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