Cover Story

Pertussis increase attributed to waning vaccine immunity

Since the 1940s, the diphtheria, tetanus and pertussis vaccine has been widely available to combat the transmission and development of pertussis — also known as whooping cough. Yet, despite the availability of this immunization, rates of this bacterial infection have been increasing since the 1990s. The most recent spike was observed in 2012, with the CDC receiving 48,277 reports of illness in the United States.

However, that number is likely to be underestimated. Although the disease is most frequently reported in infants and young children, many cases are misdiagnosed or left untreated because of the atypical presentation in vaccinated adolescents and adults, according to a review published in American Family Physician. Another study published in the LancetInfectious Diseases suggests that the global burden of pertussis is estimated at 24.1 million cases, causing 160,700 deaths in children aged younger than 5 years globally.

Source: Insight Foto for Santa Fe Institute

Benjamin Althouse, PhD, ScM, senior research scientist at the Institute for Disease Modeling, believes part of the issue of increasing frequency of pertussis in the U.S. could be due to waning immunity of acellular pertussis vaccination.

Tina Q. Tan, MD, attending physician at the division of infectious diseases and medical director of the International Patient Services Program at Ann & Robert H. Lurie Children’s Hospital of Chicago and professor of pediatrics at Northwestern University Feinberg School of Medicine, said that the age demographic has shifted within the pediatric population.

“Pertussis is a lot more common than I think people recognize among children in the U.S.,” Tan told Infectious Diseases in Children. “It is one of the vaccine-preventable diseases that we continue to see a fair amount of, even though we have very effective vaccines against it. Children between the ages of 7 and 10 years are now at much higher risk of getting pertussis disease.”

Additionally, James D. Cherry, MD, MSc, distinguished research professor at the David Geffen School of Medicine at UCLA, mentioned that a reporting bias may contribute to inaccurate rates of pertussis.

“The prevalence of pertussis varies based on reported cases, which is just the tip of the iceberg. It has roughly 3-year cycles where it increases,” he said. “The main cases of pertussis that are seen are those that are hard for people to miss. These are usually children between 1 and 10 years of age.”

Several hypotheses have been suggested as to why the number of cases have increased in a country with high rates of pediatric vaccination against pertussis, including waning immunity provided by the acellular vaccine adopted in the late 1990s and increases in nonmedical vaccine exemptions.

Infectious Diseases in Children spoke with infectious disease experts and epidemiologists to address the legitimacy of these theories, current treatment options in the wake of antimicrobial resistance and the prevention of additional outbreaks.

Signs and symptoms

Pertussis differs from many other respiratory conditions primarily because the infection is bacterial. Bordetella pertussis, a gram-negative coccobacillus and a contributor to the development of whooping cough, may spur unique presentations of disease, according to Cherry.

“With most viral infections, you have fever. This is also certainly true with bacterial infections, but with pertussis, there is no fever,” Cherry told Infectious Diseases in Children. “The only time there is fever is when there is a secondary bacterial or viral infection. The cough is also different than the cough you see with [conditions such as] bronchiolitis. With bronchiolitis, you are trapping air. With pertussis, you cough out all the air before you can take a breath. This breath leads to the ‘whoop.’”

According to the CDC, pertussis has three stages of development. The first stage of the disease is known as the catarrhal stage, says Robert W. Frenck Jr., MD, professor of pediatrics from the division of infectious diseases at Cincinnati Children’s Hospital Medical Center.

Tina Q. Tan

“In the catarrhal stage of pertussis, you just have a runny nose and a cough, which looks just like the common cold,” Frenck said in an interview with Infectious Diseases in Children. “The thing that separates pertussis from other infections [at this stage] is the chronicity. One of the names for the disease is the hundred-day cough.”

The CDC notes that some of the signs and symptoms early in the disease include a runny nose, the chance of a low-grade fever, mild and occasional cough and the occurrence of apnea in infants. After 1 or 2 weeks of mild symptoms, more severe and classic symptoms of pertussis may appear in the paroxysmal stage. These include paroxysms of coughs proceeded by a whoop, fatigue after these coughing fits and potential vomiting during or after paroxysms.

Clearing a pertussis infection requires a period of recovery that lasts 2 to 3 weeks, known as the convalescent stage. During this stage, those who were infected may become susceptible to a variety of viral and bacterial respiratory infections.

“One of the complicated things about pertussis is that most of the severe symptoms, like the ‘whoop,’ largely come from a toxin that the bacteria produce,” Samuel Scarpino, PhD, a core faculty member in the Network Science Institute at Northeastern University, said in an interview with Infectious Diseases in Children.

“Even when people are no longer infected with the bacteria and have cleared the infection, they can still have a severe cough and could be at risk of complications associated with infection,” he continued. “Often, the biggest risk for pertussis is waiting to treat until it is almost too late in respect to the amount of pertussis toxins built up inside the body.”

Treatment in the wake of resistance

To prevent transmission and severity of the disease, it is paramount to treat the patient with macrolide antibiotics as quickly as possible. According to a study published in Clinical Infectious Diseases, it is suggested that patients be treated with a macrolide antibiotic, even if the case is not confirmed through a PCR or a less-sensitive nasopharyngeal sample.

Presumptive prescription of antibiotics poses concerns given the rising rate of antibiotic resistance.

A study published in The Pediatric Infectious Disease Journal highlighted previous cases of erythromycin-resistant B. pertussis. The first case was observed in 1994 in a 2-month-old infant in Arizona. The authors of the study claim that reported erythromycin-resistant pertussis occurs infrequently in the U.S., but the frequency of erythromycin-resistant pertussis has been on the rise in other countries such as China.

According to Tan, antimicrobial resistance should be in the back of every physician’s mind, but the benefits of prompt treatment of suspected and confirmed pertussis outweigh the dangers.

“You really need to treat individuals for pertussis so that they do not spread it to other individuals,” Tan said. “If someone is suspected of having pertussis, a physician should not wait for testing to come back. They should treat them and chemoprophylax all the household contacts and other close contacts of the individual.”

James D. Cherry

Although the treatment of whooping cough is possible with macrolides, such as azithromycin, prevention is still a preferred course of action.

According to a study published in Pediatrics, the prevention of pertussis in children can begin in utero with maternal immunization. The use of tetanus toxoid, reduced diphtheria toxoid, acellular pertussis (Tdap) vaccine in pregnant women demonstrated a 91.4% efficacy within their child’s first 2 months of life and 87.9% before the infant’s first dose of diphtheria, tetanus and acellular pertussis (DTaP) vaccine. The maternal dose also provided additional protection after the infant had received DTaP dosing, making the vaccination of pregnant women routine in the U.S.

Despite high maternal and pediatric immunization rates, the frequency of pertussis in the U.S. has been increasing over several years. The CDC claims that 84.6% of children received 4+ doses of DTP, DT or DTaP in 2016.

There are a number of factors that contribute to increasing pertussis, offering several potential targets for action.

Benjamin Althouse, PhD, ScM, senior research scientist at the Institute for Disease Modeling, believes that part of the issue could be due to the waning immunity of acellular pertussis vaccination.

“There is some evidence that the protectiveness from the vaccine wanes a bit over time. You are very well protected against symptoms of the disease up until age 5 or 6,” Althouse told Infectious Diseases in Children. “The problem starts when you infect infants under 1 year when they are not fully protected from the vaccine. They have a much higher rate of hospitalization and death than the older age groups.”

Vaccination against pertussis

When immunization against pertussis became available in the 1940s, it included an entire inactive B. pertussis organism (whole cell pertussis vaccine). Despite its efficacy, WHO notes that the vaccine was associated with minor adverse reactions, including redness and swelling at the injection site and some more serious adverse reactions such as very high fever, prolonged inconsolable crying for hours, hyporesponsive episodes and agitation.

These side effects contributed to the switch to an acellular vaccine in the late 1990s, which contains approximately five proteins from the bacterium. This immunization has fewer adverse events, but evidence supports a more rapid waning immunity provided by the vaccine.

Findings published in Clinical Infectious Diseases support a distinctly increased risk of disease when children are vaccinated exclusively with an acellular series. The vaccine demonstrated less efficacy and durability than the previously used whole cell vaccine. Another study published in Pediatrics demonstrated that adolescents who received a whole cell vaccination before the implementation of the acellular vaccine had a greater level of protection from pertussis than those who received only the acellular DTaP vaccine.

“The powers that be thought that the side effects were severe enough to start using this new vaccine which had a much lower rate of side effects, but less protection against transmission or colonization,” Althouse said. “That means every child should be vaccinated. You do not want to send your kid to a day care without being protected against disease. You do not have the same level of herd immunity to protect them. It was a big trade off.”

The increase in cases, according to Scarpino, could also be attributed to asymptomatic carriers of the bacteria.

“There were a couple of studies published within the last few years in non-human primate models of pertussis infection that demonstrated the inability of the acellular vaccine to prevent infection with the pertussis bacteria,” he said. “The animals in the trial could be infected with the pertussis bacteria, although they did not have any symptoms of disease.”

“However, when these [asymptomatic carriers] were put into the same room with animals who were completely unvaccinated and naive to pertussis, those naive individuals could become infected and would develop a symptomatic form of the disease,” he continued.

Additionally, undervaccination in pocket areas, despite the CDC report that 84.6% of children aged 19 to 35 months received four or more doses of a pertussis-containing vaccine in 2016, may contribute to recent outbreaks.

“We do a fairly good job of getting younger children vaccinated by the time they reach kindergarten,” Tan said. “If you look at kindergarten vaccine rates, you are looking at percentages between 93% and 95%. A lot of that has to do with school requirements.”

However, nonmedical vaccine exemptions may be to blame for the uptick in pertussis cases. Findings published in JAMA demonstrate that the allowance of personal belief exemptions and easily obtained vaccine exemptions have higher rates of pertussis.

“I think that one of the biggest problems is that vaccines have done such an excellent job and have worked so well at eliminating disease that a lot of younger parents have never seen a natural disease,” Frenck said. “Because of that, they really do not understand how serious the natural disease can be, and they perceive that there is really no risk.”

Robert W. Frenck Jr.

“People who choose not to vaccinate their children see risks like the pain involved with getting a shot or a false increased risk of autism, but they are not seeing the benefits,” he continued. “The risks associated with pertussis [and other vaccine-preventable diseases] are significant. People used to die from these diseases, and people still do die from these diseases,” he continued.

Because it is difficult to support these hypotheses on epidemiologic data alone, Althouse suggested that more research is needed regarding the genetics of transmission. Furthermore, he mentioned that detailed household transmission studies are needed to better understand the rate of asymptomatic transmission because a dearth of information exists on the topic.

Preventing additional outbreaks

The prevention of vaccine-preventable diseases has been placed in the forefront with the rise in cases spreading throughout American schools and communities. Recognizing the symptoms early on and providing adequate care for patients presenting with pertussis symptoms will reduce the likelihood of additional infections.

“Pediatricians should have greater awareness of cough illness without fever and be more willing to get a PCR and to treat those presumptively as pertussis,” Cherry said in an interview. “Do not wait for the PCR results to come back.”

When confronted with possible pertussis infection, confirming that children and household members are sufficiently vaccinated should be the first step in preventing additional cases.

“Physicians should ensure that younger children have the doses of vaccines that they should have,” he continued. “In this case, they should have three doses in the first year, a booster dose in the second and another dose between the ages of 4 and 6 years. When you get to older patients, we give Tdap vaccines at about age 10.”

Although there are concerns about the longevity of the acellular vaccine, Scarpino stressed that the vaccine is safe and effective at preventing disease. Pediatricians are in a unique position to keep vaccination rates high in the demographic most likely to have reported cases of pertussis. Testing individuals who meet a symptom-based definition for pertussis but would not typically get tested for the infection, regardless of age, may prevent additional cases.

“There is an underappreciation of the prevalence of older children and adults,” Scarpino said. “Physicians testing older children and adults for pertussis will help make us all more aware of where infections are spreading so that we can try to minimize contact with individuals who might become infected.”

Because eradication of pertussis is not on the horizon, it is important that pediatricians stress how important vaccination is to keep children and surrounding community members healthy.

“One of the things that people need to realize is that there is only one disease that we have eliminated from the world, and that is smallpox,” Frenck said in an interview. “We are getting pretty close with polio, and we are hoping to have that eliminated soon. What is keeping these diseases away are vaccines. When you do not vaccinate, the diseases come back.” – by Katherine Bortz

Disclosures: Althouse, Cherry, Frenck and Tan report no relevant financial disclosures. Scarpino reports being a consultant for ILiAD Biotechnologies, which has a pertussis vaccine in phase 2 trials.

Since the 1940s, the diphtheria, tetanus and pertussis vaccine has been widely available to combat the transmission and development of pertussis — also known as whooping cough. Yet, despite the availability of this immunization, rates of this bacterial infection have been increasing since the 1990s. The most recent spike was observed in 2012, with the CDC receiving 48,277 reports of illness in the United States.

However, that number is likely to be underestimated. Although the disease is most frequently reported in infants and young children, many cases are misdiagnosed or left untreated because of the atypical presentation in vaccinated adolescents and adults, according to a review published in American Family Physician. Another study published in the LancetInfectious Diseases suggests that the global burden of pertussis is estimated at 24.1 million cases, causing 160,700 deaths in children aged younger than 5 years globally.

Source: Insight Foto for Santa Fe Institute

Benjamin Althouse, PhD, ScM, senior research scientist at the Institute for Disease Modeling, believes part of the issue of increasing frequency of pertussis in the U.S. could be due to waning immunity of acellular pertussis vaccination.

Tina Q. Tan, MD, attending physician at the division of infectious diseases and medical director of the International Patient Services Program at Ann & Robert H. Lurie Children’s Hospital of Chicago and professor of pediatrics at Northwestern University Feinberg School of Medicine, said that the age demographic has shifted within the pediatric population.

“Pertussis is a lot more common than I think people recognize among children in the U.S.,” Tan told Infectious Diseases in Children. “It is one of the vaccine-preventable diseases that we continue to see a fair amount of, even though we have very effective vaccines against it. Children between the ages of 7 and 10 years are now at much higher risk of getting pertussis disease.”

Additionally, James D. Cherry, MD, MSc, distinguished research professor at the David Geffen School of Medicine at UCLA, mentioned that a reporting bias may contribute to inaccurate rates of pertussis.

“The prevalence of pertussis varies based on reported cases, which is just the tip of the iceberg. It has roughly 3-year cycles where it increases,” he said. “The main cases of pertussis that are seen are those that are hard for people to miss. These are usually children between 1 and 10 years of age.”

Several hypotheses have been suggested as to why the number of cases have increased in a country with high rates of pediatric vaccination against pertussis, including waning immunity provided by the acellular vaccine adopted in the late 1990s and increases in nonmedical vaccine exemptions.

PAGE BREAK

Infectious Diseases in Children spoke with infectious disease experts and epidemiologists to address the legitimacy of these theories, current treatment options in the wake of antimicrobial resistance and the prevention of additional outbreaks.

Signs and symptoms

Pertussis differs from many other respiratory conditions primarily because the infection is bacterial. Bordetella pertussis, a gram-negative coccobacillus and a contributor to the development of whooping cough, may spur unique presentations of disease, according to Cherry.

“With most viral infections, you have fever. This is also certainly true with bacterial infections, but with pertussis, there is no fever,” Cherry told Infectious Diseases in Children. “The only time there is fever is when there is a secondary bacterial or viral infection. The cough is also different than the cough you see with [conditions such as] bronchiolitis. With bronchiolitis, you are trapping air. With pertussis, you cough out all the air before you can take a breath. This breath leads to the ‘whoop.’”

According to the CDC, pertussis has three stages of development. The first stage of the disease is known as the catarrhal stage, says Robert W. Frenck Jr., MD, professor of pediatrics from the division of infectious diseases at Cincinnati Children’s Hospital Medical Center.

Tina Q. Tan

“In the catarrhal stage of pertussis, you just have a runny nose and a cough, which looks just like the common cold,” Frenck said in an interview with Infectious Diseases in Children. “The thing that separates pertussis from other infections [at this stage] is the chronicity. One of the names for the disease is the hundred-day cough.”

The CDC notes that some of the signs and symptoms early in the disease include a runny nose, the chance of a low-grade fever, mild and occasional cough and the occurrence of apnea in infants. After 1 or 2 weeks of mild symptoms, more severe and classic symptoms of pertussis may appear in the paroxysmal stage. These include paroxysms of coughs proceeded by a whoop, fatigue after these coughing fits and potential vomiting during or after paroxysms.

Clearing a pertussis infection requires a period of recovery that lasts 2 to 3 weeks, known as the convalescent stage. During this stage, those who were infected may become susceptible to a variety of viral and bacterial respiratory infections.

“One of the complicated things about pertussis is that most of the severe symptoms, like the ‘whoop,’ largely come from a toxin that the bacteria produce,” Samuel Scarpino, PhD, a core faculty member in the Network Science Institute at Northeastern University, said in an interview with Infectious Diseases in Children.

PAGE BREAK

“Even when people are no longer infected with the bacteria and have cleared the infection, they can still have a severe cough and could be at risk of complications associated with infection,” he continued. “Often, the biggest risk for pertussis is waiting to treat until it is almost too late in respect to the amount of pertussis toxins built up inside the body.”

Treatment in the wake of resistance

To prevent transmission and severity of the disease, it is paramount to treat the patient with macrolide antibiotics as quickly as possible. According to a study published in Clinical Infectious Diseases, it is suggested that patients be treated with a macrolide antibiotic, even if the case is not confirmed through a PCR or a less-sensitive nasopharyngeal sample.

Presumptive prescription of antibiotics poses concerns given the rising rate of antibiotic resistance.

A study published in The Pediatric Infectious Disease Journal highlighted previous cases of erythromycin-resistant B. pertussis. The first case was observed in 1994 in a 2-month-old infant in Arizona. The authors of the study claim that reported erythromycin-resistant pertussis occurs infrequently in the U.S., but the frequency of erythromycin-resistant pertussis has been on the rise in other countries such as China.

According to Tan, antimicrobial resistance should be in the back of every physician’s mind, but the benefits of prompt treatment of suspected and confirmed pertussis outweigh the dangers.

“You really need to treat individuals for pertussis so that they do not spread it to other individuals,” Tan said. “If someone is suspected of having pertussis, a physician should not wait for testing to come back. They should treat them and chemoprophylax all the household contacts and other close contacts of the individual.”

James D. Cherry

Although the treatment of whooping cough is possible with macrolides, such as azithromycin, prevention is still a preferred course of action.

According to a study published in Pediatrics, the prevention of pertussis in children can begin in utero with maternal immunization. The use of tetanus toxoid, reduced diphtheria toxoid, acellular pertussis (Tdap) vaccine in pregnant women demonstrated a 91.4% efficacy within their child’s first 2 months of life and 87.9% before the infant’s first dose of diphtheria, tetanus and acellular pertussis (DTaP) vaccine. The maternal dose also provided additional protection after the infant had received DTaP dosing, making the vaccination of pregnant women routine in the U.S.

Despite high maternal and pediatric immunization rates, the frequency of pertussis in the U.S. has been increasing over several years. The CDC claims that 84.6% of children received 4+ doses of DTP, DT or DTaP in 2016.

PAGE BREAK

There are a number of factors that contribute to increasing pertussis, offering several potential targets for action.

Benjamin Althouse, PhD, ScM, senior research scientist at the Institute for Disease Modeling, believes that part of the issue could be due to the waning immunity of acellular pertussis vaccination.

“There is some evidence that the protectiveness from the vaccine wanes a bit over time. You are very well protected against symptoms of the disease up until age 5 or 6,” Althouse told Infectious Diseases in Children. “The problem starts when you infect infants under 1 year when they are not fully protected from the vaccine. They have a much higher rate of hospitalization and death than the older age groups.”

Vaccination against pertussis

When immunization against pertussis became available in the 1940s, it included an entire inactive B. pertussis organism (whole cell pertussis vaccine). Despite its efficacy, WHO notes that the vaccine was associated with minor adverse reactions, including redness and swelling at the injection site and some more serious adverse reactions such as very high fever, prolonged inconsolable crying for hours, hyporesponsive episodes and agitation.

These side effects contributed to the switch to an acellular vaccine in the late 1990s, which contains approximately five proteins from the bacterium. This immunization has fewer adverse events, but evidence supports a more rapid waning immunity provided by the vaccine.

Findings published in Clinical Infectious Diseases support a distinctly increased risk of disease when children are vaccinated exclusively with an acellular series. The vaccine demonstrated less efficacy and durability than the previously used whole cell vaccine. Another study published in Pediatrics demonstrated that adolescents who received a whole cell vaccination before the implementation of the acellular vaccine had a greater level of protection from pertussis than those who received only the acellular DTaP vaccine.

“The powers that be thought that the side effects were severe enough to start using this new vaccine which had a much lower rate of side effects, but less protection against transmission or colonization,” Althouse said. “That means every child should be vaccinated. You do not want to send your kid to a day care without being protected against disease. You do not have the same level of herd immunity to protect them. It was a big trade off.”

The increase in cases, according to Scarpino, could also be attributed to asymptomatic carriers of the bacteria.

“There were a couple of studies published within the last few years in non-human primate models of pertussis infection that demonstrated the inability of the acellular vaccine to prevent infection with the pertussis bacteria,” he said. “The animals in the trial could be infected with the pertussis bacteria, although they did not have any symptoms of disease.”

PAGE BREAK

“However, when these [asymptomatic carriers] were put into the same room with animals who were completely unvaccinated and naive to pertussis, those naive individuals could become infected and would develop a symptomatic form of the disease,” he continued.

Additionally, undervaccination in pocket areas, despite the CDC report that 84.6% of children aged 19 to 35 months received four or more doses of a pertussis-containing vaccine in 2016, may contribute to recent outbreaks.

“We do a fairly good job of getting younger children vaccinated by the time they reach kindergarten,” Tan said. “If you look at kindergarten vaccine rates, you are looking at percentages between 93% and 95%. A lot of that has to do with school requirements.”

However, nonmedical vaccine exemptions may be to blame for the uptick in pertussis cases. Findings published in JAMA demonstrate that the allowance of personal belief exemptions and easily obtained vaccine exemptions have higher rates of pertussis.

“I think that one of the biggest problems is that vaccines have done such an excellent job and have worked so well at eliminating disease that a lot of younger parents have never seen a natural disease,” Frenck said. “Because of that, they really do not understand how serious the natural disease can be, and they perceive that there is really no risk.”

Robert W. Frenck Jr.

“People who choose not to vaccinate their children see risks like the pain involved with getting a shot or a false increased risk of autism, but they are not seeing the benefits,” he continued. “The risks associated with pertussis [and other vaccine-preventable diseases] are significant. People used to die from these diseases, and people still do die from these diseases,” he continued.

Because it is difficult to support these hypotheses on epidemiologic data alone, Althouse suggested that more research is needed regarding the genetics of transmission. Furthermore, he mentioned that detailed household transmission studies are needed to better understand the rate of asymptomatic transmission because a dearth of information exists on the topic.

Preventing additional outbreaks

The prevention of vaccine-preventable diseases has been placed in the forefront with the rise in cases spreading throughout American schools and communities. Recognizing the symptoms early on and providing adequate care for patients presenting with pertussis symptoms will reduce the likelihood of additional infections.

“Pediatricians should have greater awareness of cough illness without fever and be more willing to get a PCR and to treat those presumptively as pertussis,” Cherry said in an interview. “Do not wait for the PCR results to come back.”

PAGE BREAK

When confronted with possible pertussis infection, confirming that children and household members are sufficiently vaccinated should be the first step in preventing additional cases.

“Physicians should ensure that younger children have the doses of vaccines that they should have,” he continued. “In this case, they should have three doses in the first year, a booster dose in the second and another dose between the ages of 4 and 6 years. When you get to older patients, we give Tdap vaccines at about age 10.”

Although there are concerns about the longevity of the acellular vaccine, Scarpino stressed that the vaccine is safe and effective at preventing disease. Pediatricians are in a unique position to keep vaccination rates high in the demographic most likely to have reported cases of pertussis. Testing individuals who meet a symptom-based definition for pertussis but would not typically get tested for the infection, regardless of age, may prevent additional cases.

“There is an underappreciation of the prevalence of older children and adults,” Scarpino said. “Physicians testing older children and adults for pertussis will help make us all more aware of where infections are spreading so that we can try to minimize contact with individuals who might become infected.”

Because eradication of pertussis is not on the horizon, it is important that pediatricians stress how important vaccination is to keep children and surrounding community members healthy.

“One of the things that people need to realize is that there is only one disease that we have eliminated from the world, and that is smallpox,” Frenck said in an interview. “We are getting pretty close with polio, and we are hoping to have that eliminated soon. What is keeping these diseases away are vaccines. When you do not vaccinate, the diseases come back.” – by Katherine Bortz

Disclosures: Althouse, Cherry, Frenck and Tan report no relevant financial disclosures. Scarpino reports being a consultant for ILiAD Biotechnologies, which has a pertussis vaccine in phase 2 trials.