Myriad causes contributed to California pertussis outbreak

There are a number of factors that contributed to the recent pertussis outbreak in California, including waning immunity to diphtheria and tetanus toxoids and acellular pertussis vaccines and a lack of vaccination among certain populations, according to the latest data presented at recent meetings.

Results of several studies presented during the 49th Annual Meeting of the Infectious Diseases Society of America in Boston indicated that the effectiveness of acellular pertussis vaccines wanes substantially over time, but that the tetanus-diphtheria-pertussis vaccines, which are recommended for adolescents, are helpful in boosting protection rates overall. That is the hope of the Advisory Committee on Immunization Practices, which recently recommended Tdap for pregnant women, besides adolescents.

“With California having recently experienced the worst whooping cough outbreak in 60 years, it is all of our hopes that women will take advantage of this opportunity in the same manner by which they do other things for the benefit of their babies,” David W. Kimberlin, MD, who is an Infectious Diseases in Children Editorial Board member and an AAP committee representative at the ACIP, said in an interview.

According to the CDC, 27,550 cases of pertussis were reported in the United States in 2010, with about 10,000 of those occurring in California. Although the outbreak in California has diminished substantially — as of September, health officials reported about 2,500 cases of pertussis in the state in 2011.

“These numbers are still much higher than we’d like to see,” said Kathryn M. Edwards, MD, who is also an Infectious Diseases in Children Editorial Board member. And that, Edwards said, is the reason many health experts are working to determine the reasons why this outbreak has occurred, and what can be done to stop it. Edwards is the chair in pediatrics at Vanderbilt University, Nashville, Tenn.

Origins of outbreak

Results of several studies presented at the annual IDSA meeting indicated that use of acellular pertussis vaccines likely played a key role in the California outbreak.

A late-breaker presentation by Kaiser Permanente researcher Roger P. Baxter, MD, and colleagues concluded that “acellular vaccines appeared to provide less protection than the whole-cell vaccines they replaced, and their effectiveness may wane substantially over time.”

“The efficacy of the fifth dose of DTaP wanes by more than 40% per year,” Baxter told Infectious Diseases in Children.

Irini Daskalaki, MD, of the Philadelphia Department of Public Health, presented data that backed those findings. In this paper, which looked retrospectively at 43 children reported to a city immunization registry, the researchers concluded: “Even in a very limited window of risk (5 years), children who received their last childhood DTaP vaccination at an earlier age tended to be at increased risk for pertussis. This increased risk for pertussis in 7- to 11-year-old children is likely due to waning immunity, which could be minimized through administration of DTaP closer to 6 years of age rather than at 4 years of age.”

Sara Tartof, PhD, MPH, an epidemiologist with the CDC, reached similar conclusions in her presentation at IDSA: “Incidence rates of pertussis increase in magnitude over the 5 years following completion of the five-dose DTaP series, suggesting waning immunity 3 to 5 years after the completion of the DTaP series.”

In related study data also presented at IDSA, CDC researchers calculated that vaccine effectiveness estimates “across all ages for five DTaP doses compared with zero doses was 85.9% (95% CI, 75.6-91.9). The recommended childhood vaccination schedule for pertussis permits a four-dose schedule if the fourth dose is received after a child’s 4th birthday. The preliminary [vaccine effectiveness] estimate across all ages for the four-dose schedule compared with zero doses was 80.4% (95% CI, 62.5-89.8).”

For the five doses, the preliminary vaccine effectiveness estimate compared with zero doses decreased from 94.7% in children aged 4 to 5 years to 84.9% in children aged 6 to 7 years, and to 81.1% in children aged 8 to 10 years.

These findings led the CDC researchers on that paper to conclude: “Although overall vaccine efficacy is good, the relative drop of 14% from the 4- to 5-year-olds to the 8- to 10-year-olds suggests that waning of immunity is occurring.”

In an interview with Infectious Diseases in Children, Tartof said her study looked at data on children born between 1998 and 2003 who had five doses of DTaP recorded in the Minnesota Immunization Information Connection, with the fifth dose received between the ages of 4 and 6 years. The researchers used statewide pertussis surveillance data between 2004 and 2010 to identify those children within the cohort who developed pertussis anyway, and “in the 5 years of follow-up beginning at the time of receipt of their fifth DTaP dose, 358 cases of pertussis developed in this cohort. The incidence rates of pertussis in these 1 to 5 years of follow-up were 22.5 (16.7-29.9); 29.1 (22.3-37.3); 42.4 (33.8-52.4); 54.4 (43.5-67.2); and 78.2 (63.2-95.7) respectively. Analyses to calculate adjusted relative rates are ongoing.”

Tartof said her data, taken together with other data presented at IDSA, suggest that “we are seeing a shift in the epidemiology of pertussis to the 7- to 10-year-olds, which is different than what we saw in 2005, which was more pertussis in the 11- to 12-year-olds.”

In a talk about the shifting epidemiology of pertussis during the IDSA meeting, Stanley A. Plotkin, MD, said pertussis is an important public health problem in Japan and Switzerland, as well, despite sustaining high vaccination rates. The evidence that acellular vaccines give less lasting immunity than whole-cell vaccines is accumulating in many countries throughout the world, and it is necessary to evaluate whether improved acellular pertussis vaccines are needed for better control of pertussis, Plotkin said.

“Age distribution of pertussis seems to have shifted toward older children, adolescents and adults in countries with high vaccine coverage,” said Plotkin, emeritus professor of the University of Pennsylvania and adjunct professor at Johns Hopkins University. “Decreased transmission in childhood is leading to a lower force of infection, less natural boosting due to subclinical infections and to more susceptible older people.”

But, even with waning immunity, Baxter said vaccination makes a difference. Data in his study suggest that “those children who were not up-to-date were twice as likely to have pertussis as those children who were up-to-date.”

The researchers said the pattern of pertussis incidence by age “closely paralleled the age-related pattern of acellular vaccine use during infancy.” Baxter, who is co-director of the Kaiser Permanente Vaccine Study Center, said this data suggests that more education is needed on vaccine refusal.

Strategies for intervention

Baxter and colleagues also said Tdap vaccination was 55% effective against pertussis (95% CI, 37-61). ACIP members said they are hoping that this booster effect will have a positive result on overall pertussis rates, as they recently recommended TDaP for all pregnant women and have built that recommendation into the 2012 adult immunization schedule.

Sarah S. Long, MD, who is chief of infectious diseases at St. Christopher’s Hospital for Children in Philadelphia, said the changes recommend that all pregnant women who have been pregnant for more than 20 weeks should receive Tdap.

Long said these recommendations follow data by the CDC indicating that more than 80% of expectant mothers are willing to get the vaccine, and that a “cocooning strategy,” which was recommended by the CDC in 2006, did not sway vaccination rates in family members of new infants.

“This strategy has been completely unsuccessful,” Long said during a recent presentation at the AAP National Conference and Exhibition held in Boston.

Edwards said this cocooning strategy is difficult to enforce: “Cocooning is hard to do. Dr. Carol Baker [who is head of the department of pediatric infectious diseases at Baylor College of Medicine, Houston and also sits on the ACIP] has data that show that the cocoon strategy didn’t work for one hospital, and that it was often just a function of some people being missed for vaccination during that postpartum period. Even missing one can lead to failures with this strategy.”

Long said many pregnant women are receiving the tetanus and diphtheria vaccine while pregnant already, and adding the pertussis component is expected to provide at least some antibodies to neonates.

She also said this change in strategy is important because most pertussis-related morbidity and mortality in children occur in those babies aged younger than 4 months, or those children who are too young to be protected by DTaP vaccination.

There may be some issues once pregnancy Tdap recommendations are put into place, including a possible blunting of immune response to the babies’ first DTaP vaccination in the first 2 to 6 months of life, since this has already been demonstrated in some studies, according to Long. However, the data seem to indicate that although blunted responses occur initially to those babies who are exposed to Tdap in utero, their antibodies seem to catch up to those infants who were not exposed in utero by 15 to 18 months of age.

The early blunting is not likely to be a major cause of concern, Long said, because it does not matter where the infant’s antibody comes from as long as the infant has some. And this strategy is likely to protect very young infants from death.

According to Long, “changes in the recommendations for pertussis vaccine are needed because disease incidence in infants is rising and disease is severe.”

Targeting pregnant women for vaccination is a good strategy because other data have shown that giving pertussis vaccines at birth leads to interference with other vaccines, specifically Haemophilus influenzae type b, Long said.

That is why the primary series currently includes four doses given at ages 2, 4, 6 and 15 to 18 months. A fifth (booster) dose is recommended when the child is aged 4 to 6 years. Also, a booster doses of Tdap are recommended at ages 11 to 12 years.

Continue to immunize

Howard Backer, MD, MPH, who is director of the California Department of Public Health, said the best way for pediatricians to assist in halting the outbreak is to encourage parents to ensure their adolescent’s immunizations are up-to-date in compliance with a new California law that went into effect earlier this year. The law, AB 354, requires documentation of an adolescent pertussis booster shot before school entry. More than 1 million students statewide remained unvaccinated before the fall semester.

“Vaccination, including critical booster shots, is the best defense against pertussis,” Backer said. “Parents of seventh- to 12th-graders must ensure that their children receive the necessary booster shot to avoid a delay in having their children start school.”

Tartof said more data are probably needed before a policy shift is made to adding another dose of Tdap in the 7- to 10-year-old groups.

“There are a number of considerations before recommending a change in vaccination policy, including cost, and what is driving this waning immunity. Is it the manufacturer, the components of the vaccine, and all of this needs to be studied,” she said, adding that she hopes to expand her data beyond her cohort to other states.

“If women are not vaccinated by the time their babies are born, they still need to get vaccinated postpartum because using that cocoon strategy makes them less likely to bring pertussis home to their infant,” Edwards said.

A new outbreak

What started out as a small pocket of about a dozen patients with pertussis in one area of Long Island, N.Y., has spread and now includes more than 200 people, according to the Suffolk County Department of Health Services.

Dennis Russo, MD, director of public health emergency preparedness at the Suffolk County Department of Health Services, said Suffolk County has the highest number of cases reported since 2006. However, despite the rise in cases, Russo said the vaccine is still effective and people in New York should continue to get the vaccine.

“We have 1.5 million people across the county, and about 210 cases,” Russo said. “Data indicate the vaccine is 80% effective, which means that everyone should be vaccinated because it is still a very good vaccine.” – by Colleen Zacharyczuk

For more information:

• Baxter R. #LB-6.
• Daskalaki I. #762.
• Misegades LK. #763.
• Tartof S. #764. All presented at: IDSA 49th Annual Meeting; Oct. 20-23, 2011; Boston.
• Long S. #F2120. Presented at: AAP National Conference and Exhibition; Oct. 15-18, 2011; Boston.

Disclosure: Dr. Baxter reports receiving research funds from Sanofi. The other researchers report no relevant financial disclosures.

Will giving Tdap to pregnant women help with the current pertussis epidemic in California?

The switch in strategy will decrease morbidity and mortality related to pertussis.

Pertussis infects people of all ages, but historically, almost all the deaths are in young infants. As a result, one important goal of our pertussis immunization strategy is to minimize infection in infants. Where do babies get their pertussis? From their parents, siblings and grandparents in 75% of the cases (Bisgard KM. Pediatr Infect Dis J. 2004;23:985-989).

It is unclear how effective the cocooning strategy has been, but what is clear is that such a strategy is difficult to implement and the potential benefits have not been fully realized. In trying to immunize all of the family contacts of a newborn, providers have encountered barriers that include lack of health care access; inadequate reimbursement; restrictions on outpatient procedures in inpatient settings; and lack of knowledge about the importance of vaccine among family members. Health care workers who see young infants are another potential source of infection, and unfortunately, this group is inadequately immunized as well.

The ACIP felt that the cocooning strategy was not enough to protect babies, so the members voted to recommend immunization during pregnancy. Vaccination during pregnancy appears safe and the concept is that pregnancy immunization will protect both the mother and the baby from day 1 of life. There is good evidence that maternal antibody reaches the baby, and it is likely to protect during the most vulnerable first months of life. The only concern is that this same maternal antibody may blunt the baby’s subsequent response to their own DTaP series. Studies are ongoing to assess the degree of potential blunting, but in the meantime, ACIP felt it was more important to protect babies right at birth. Even if blunting occurs, the effect will be to shift cases that would have occurred in the first month of life to a later age when pertussis is not fatal. I am sure that this strategy will decrease deaths from pertussis.

Mark H. Sawyer, MD, is professor of clinical pediatrics and pediatric infectious disease specialist at the University of California at San Diego School of Medicine & Rady Children’s Hospital in San Diego. Disclosure: Dr. Sawyer reports no relevant financial disclosures.

The switch in immunization strategy was necessary and will work if the blunting dissipates.

The cocoon strategy was designed to immunize adults (and siblings) who are in close contact with newborn infants, with the most important target being the parents. Immunizing women immediately postpartum, although recommended, has been logistically difficult to implement and still may leave infants susceptible for up to 2 weeks (until the mother’s antibody levels rise post-vaccination).

Immunization of women during the latter half of pregnancy elicits high levels of anti-pertussis antibodies, which are then transferred to the fetus across the placenta. Infants of women immunized during pregnancy have high levels of antibodies in cord blood, which may help protect them during the vulnerable first weeks of life, until they produce their own antibodies in response to the infant immunization series. However, there are preliminary data that suggest that these high levels of antibody may lead to somewhat lower levels after the primary immunization series.

The new policy of immunizing women with Tdap during pregnancy may improve the protection of young infants who are at the greatest risk of severe disease and death from pertussis. It will be important to closely monitor the epidemiology of pertussis using active surveillance to determine whether these beneficial effects are realized and to see whether the potential for lower antibody levels in the second half of the first year of life has any detrimental effect on the rates of disease in these older infants.

However, given the dramatic increase in pertussis deaths, the change in policy was timely and appropriate.

Scott A. Halperin, MD, is professor of pediatrics and head of pediatric infectious diseases, as well as director of the Canadian Center for Vaccinology at Dalhousie University in Halifax, Nova Scotia, Canada. Disclosure: Dr. Halperin reports no relevant financial disclosures.

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