Add pertussis, or whooping cough, to the list of respiratory infections that plummeted during the COVID-19 pandemic and began to surge during its final year.

As with the other respiratory infections, pertussis cases, caused by the bacterium Bordetella pertussis and spread via airborne droplets, likely bottomed out during the pandemic at least in part because of measures taken to stop the spread of SARS-CoV-2, such as remote learning.

In 2019, more than 18鈥�000 pertussis cases to the US Centers for Disease Control and Prevention (CDC).

Then, in January 2020, the national case definition of pertussis, which involves laboratory and clinical criteria, was revised to be more sensitive, so an increase in cases was expected that year, the CDC鈥檚 Susan Hariri, PhD, noted in June at the International Bordetella Symposium in Prague.

But the revision coincided with the beginning of the COVID-19 pandemic. Instead of increasing, the number of pertussis cases fell to 6124 in 2020 and to 2116 in 2021.

This year, however, pertussis is on track to surpass the number of cases reported in 2019. As of September 28, 16鈥�375 cases had been reported this year鈥攎ore than 4 times the cases that had been reported by the same date last year, according to .

The true population burden of pertussis likely is underestimated, Hariri told members of the US Food and Drug Administration鈥檚 Vaccines and Related Biological Products Advisory Committee (VRBPAC) at a .

Pertussis is underdiagnosed because its early symptoms resemble those of other respiratory infections, and diagnostic tests aren鈥檛 as reliable later in the disease鈥檚 course, Hariri explained at the meeting. And, she said, pertussis is underreported because milder cases might not meet the case definition for reporting. Antibiotics are effective in preventing or reducing the severity of pertussis infamous 鈥溾�� but only if given in the early days of infection, when it can be mistaken for a cold.

Reasons for the pertussis resurgence aren鈥檛 fully understood, but they鈥檙e thought to include waning of protection by the current vaccine. Although it has fewer adverse effects, the vaccine doesn鈥檛 protect against transmission or provide as long-lasting immunity as its predecessor, Hariri noted at the FDA advisory committee meeting. On top of that, she said, B pertussis may be changing to resist vaccines, and improved diagnostic tests and increased awareness and testing may be identifying cases that previously would have gone unreported.

And although steps taken to stop the spread of SARS-CoV-2 are thought to have contributed to far fewer cases of pertussis and other respiratory infections, the pandemic also was associated with declines in vaccine coverage among US children younger than 2 years due to major disruptions in primary care, according to an published in the Morbidity and Mortality Weekly Report (MMWR) in September.

The pertussis vaccine is combined with the tetanus and diphtheria vaccine into diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccines, 5 doses of which are recommended for infants and children aged 2 years through 6 years. Tetanus, diphtheria, and pertussis (Tdap) vaccines are recommended as a single dose for all adolescents aged 11 to 12 years and for pregnant people.

The proportion of children born in 2020-2021 who received 3 or more DTaP doses declined to 92.5%, 1.8 percentage points lower than in 2018-2019, according to the MMWR article. The number who received 4 or more doses fell to 79.3%, a dip of 2.5 percentage points from 2018-2019.

In addition, immunization rates are not optimal among pregnant people, for whom pertussis vaccination is recommended to protect young infants. The has long been in children younger than a year old, according to the CDC.

For decades after its introduction in the late 1940s, the pertussis vaccine was a whole-cell vaccine, part of the diphtheria-tetanus-pertussis (DTP) vaccine that contained inactivated B pertussis bacteria. It was highly reactogenic, causing fever, injection-site swelling and pain, and, less commonly, febrile seizures.

Widespread publicity about safety concerns led to of the whole-cell pertussis vaccine. The acellular pertussis vaccine, which contains fewer antigens, replaced the whole-cell vaccine in the US and many other countries in the 1990s.

But there was a cost. 鈥淭o some extent, we traded efficacy for safety,鈥� said Paul Offit, MD, a VRBPAC member and codeveloper of the rotavirus vaccine.

Protection from both types of pertussis vaccines as well as from pertussis infection eventually wanes. More than 40% of infants and children 6 months to 6 years old who were reported to have pertussis in 2023 were up-to-date with their DTaP vaccines, according to . Data often are missing, though, 鈥渨hich can cause misinterpretation,鈥� CDC spokesperson Jasmine Reed said in an email.

There鈥檚 been no indication that the proportion of US pertussis cases among people who are fully vaccinated compared with those who aren鈥檛 has changed in recent years, she wrote. 鈥淏ecause pertussis immunity wanes over time, cases among fully vaccinated people are expected,鈥� Reed explained. 鈥淗owever, those who are unvaccinated are more likely to contract pertussis and have more severe disease than those who are fully vaccinated.鈥�

The data bear this out. Before pertussis vaccines became available, were reported annually in the US.

Work to develop a more effective pertussis vaccine with an acceptable safety profile is ongoing.

For example, preclinical murine have shown that a multivalent messenger RNA DTP vaccine induced antigen-specific antibodies and memory T cells and protected mice from infection when they were exposed to B pertussis strains.

Clinical trials of a new pertussis vaccine are trickier. One reason is that there is no established immunologic marker that predicts protection for pertussis, FDA scientist Tod Merkel, PhD, at the advisory committee meeting.

Another reason, Offit explained, is that 鈥樷�橻i]n order to get a vaccine on the market, you have to show that your vaccine is at least no worse鈥� than vaccines that are already available. But he said he wondered whether investigators would want to randomize trial participants to get an experimental vaccine with unknown efficacy when a good vaccine is already on the market.

鈥淭he problem is that we have a vaccine that if it鈥檚 given鈥�it will prevent deaths, and it will prevent severe disease,鈥� said Kathryn Edwards, MD, a professor emeritus of pediatrics in the division of infectious diseases at the Vanderbilt University School of Medicine, who has conducted many vaccine trials. 鈥淭esting a new vaccine within that context is not easy.鈥�

One option, which was discussed at the September 20 FDA advisory committee meeting, is , in which volunteers receive a vaccine and then are challenged with the pathogen it targets to see if they become sick.

Researchers used a , also called a controlled human infection model, to compare an intranasal vaccine with a Tdap vaccine. The intranasal vaccine, from Florida-based ILiAD Biotechnologies, uses an inactivated live B pertussis strain developed at the Institute Pasteur de Lille and Inserm, the French National Institute of Health and Medical Research.

Participants in the phase 2b trial were healthy adults, who are less likely to develop severe disease from pertussis infection. The study found that the intranasal vaccine seemed to be safe and well tolerated and evoked 鈥渂road, robust, and sustained mucosal and systemic immune responses,鈥� the researchers in 2023.

鈥淚鈥檓 curious to see whether this works out,鈥� said Offit, who is a professor of vaccinology and of pediatrics at the University of Pennsylvania鈥檚 Perelman School of Medicine and director of the Vaccine Education Center at Children's Hospital of Philadelphia. He noted that FluMist, the live weakened intranasal influenza vaccine, 鈥渉asn鈥檛 exactly been a gamechanger.鈥�

Edwards and her coauthor and Vanderbilt colleague Michael Decker, MD, MPH, pointed out in an that ILiAD鈥檚 intranasal vaccine and the Tdap vaccine each had strong points. The intranasal vaccine induced pertussis-specific antibodies in the mucosa, which Tdap failed to do consistently, but Tdap induced significantly higher levels of pertussis antibodies in serum. However, the trial wasn鈥檛 designed to show how durable the intranasal vaccine鈥檚 benefits are, the editorial noted.

鈥淸U]sing both vaccines in concert might preserve the benefits, while addressing some of the deficiencies, associated with parenteral DTaP vaccines,鈥� Edwards and Decker concluded.

Meanwhile, Edwards told JAMA Medical News, 鈥渦ntil we have new vaccines, we need to use the ones we have.鈥�

Infants who are too young to receive their first DTaP dose are the most vulnerable to severe disease and death from pertussis infection. Their tiny tracheas can become blocked with thick mucus, Offit explained.

鈥淚 think people don鈥檛 understand the severity of pertussis in babies,鈥� Edwards noted. Because infected infants have difficulty breathing, they can develop right heart failure, she said, adding that 2 children in the US have died of pertussis this year.

To protect the youngest infants, the CDC in 2012 that all pregnant people receive a dose of Tdap during weeks 27 through 36 of their pregnancy, the earlier during that period the better.

And yet, according to , only about 55% of pregnant people overall receive a dose of Tdap; coverage is lowest among Black pregnant people, only about 31% of whom received Tdap. A published in February provided more evidence that among pregnant people, Black individuals are the least likely to receive Tdap.

Many Black pregnant people 鈥渞eport experiencing mistreatment and structural and interpersonal racism during pregnancy and delivery,鈥� CDC spokesperson Reed noted in an email. 鈥淒uring ongoing nationwide Black maternal health and infant mortality crises, vaccination during pregnancy offers an important opportunity to increase protection for Black pregnant people and their babies.鈥�

With the goal of increasing Tdap, COVID-19, and influenza vaccination among Black pregnant people, the CDC this year launched the campaign. The campaign notes that has shown that many pregnant people describe their clinician鈥檚 recommendation to get vaccinated as an important motivator.

As Hariri told the FDA advisory committee members, pertussis postpandemic resurgence serves as a reminder that 鈥渢his disease is incompletely controlled and remains a significant public health problem.鈥�

Published Online: October 25, 2024. doi:10.1001/jama.2024.22533

Conflict of Interest Disclosures: Dr Edwards reported receiving grants from the National Institutes of Health and the CDC and serving as a consultant to Dynavax and AstraZeneca and as a member of the data and safety monitoring board for Sanofi, X-4 Pharma, Seqirus, Moderna, Pfizer, Merck, Roche, Novavax, and the Brighton Collaboration. No other disclosures were reported.