Pertussis resurged over the last decade in most countries that replaced the traditional whole-cell pertussis vaccines (wP) by the less reactogenic acellular pertussis vaccines (aP). The aP vaccines induce a Th2-polarized immune response and by a yet unknown mechanism hamper the clearance of Bordetella pertussis from infected nasopharyngeal mucosa. The aP-induced pertussis toxin-neutralizing antibodies effectively prevent the life-threatening pertussis pneumonia in infants, but aP-elicited immunity fails to prevent infection of nasopharyngeal mucosa and transmission of B. pertussis. In contrast, the more reactogenic traditional wP vaccines, alike natural infection, elicit a broad antibody response and trigger a Th1/Th17-polarized T cell immunity. We tackled here the reactogenicity of the conventional wP vaccines by genetic modification of the Fim2 and Fim3-producing B. pertussis strains used for wP vaccine manufacturing. Mutations were introduced into the genomes of vaccine strains (i) to reduce the TLR4 signaling potency of the lipid A of B. pertussis lipooligosaccharide (ΔlgmB), (ii) eliminate the enzymatic (immunosuppressive) activity of the pertussis toxin (PtxS1-R9K/E129G), and (iii) ablate the production of the dermonecrotic toxin (Δdnt). Experimental alum-adjuvanted wP vaccines prepared from such triply modified bacteria exhibited a reduced pyrogenicity in rabbits and a reduced systemic toxicity in mice, while conferring a comparable protection from B. pertussis infection as the unmodified wP vaccine.IMPORTANCEThe occasionally severe adverse reactions associated with some lots of the whole-cell pertussis vaccine (wP) led the industrialized nations to switch to the use of less reactogenic acellular pertussis vaccines that confer shorter-lasting protection. This yielded whooping cough resurgence and large whooping cough outbreaks are currently sweeping throughout European countries, calling for the replacement of the pertussis vaccine component of pediatric hexavaccines by an improved wP vaccine. We show that genetic detoxification of the Bordetella pertussis bacteria used for wP preparation yields a reduced reactogenicity wP vaccine that exhibits a reduced systemic toxicity in mice and reduced pyrogenicity in rabbits, while retaining high immunogenicity and protective potency in the mouse model of pneumonic infection by B. pertussis. This result has now been confirmed in a nonhuman primate model of B. pertussis infection of olive baboons, paving the way for the development of the next generation of pertussis vaccines.

• Klíčová slova
• Bordetella pertussis, dermonecrotic toxin, immunogenicity, lipooligosaccharide, pertussis toxin, protection, reactogenicity, whole-cell vaccine, whooping cough,
• MeSH
• antigeny bakteriální MeSH
• Bordetella pertussis * imunologie   genetika   MeSH
• faktory virulence rodu Bordetella genetika   imunologie   MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• pertuse * prevence a kontrola   imunologie   MeSH
• pertusová vakcína * imunologie   genetika   aplikace a dávkování   MeSH
• proteiny fimbrií genetika   imunologie   MeSH
• protilátky bakteriální krev   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny bakteriální MeSH
• faktory virulence rodu Bordetella MeSH
• fim2 protein, Bordetella MeSH Prohlížeč
• fim3 protein, Bordetella MeSH Prohlížeč
• pertusová vakcína * MeSH
• proteiny fimbrií MeSH
• protilátky bakteriální MeSH

Whole-cell pertussis (wP) vaccines introduced in the 1940s led to a dramatic reduction of pertussis incidence and are still widely used in low- and middle-income countries (LMICs) worldwide. The reactogenicity of wP vaccines resulted in reduced public acceptance, which drove the development and introduction of acellular pertussis (aP) vaccines in high-income countries in the 1990s. Increased incidence of pertussis disease has been observed in high-income countries following the introduction of aP vaccines despite near universal rates of pediatric vaccination. These increases are attributed to the reduced protection against colonization, carriage, and transmission as well as reduced duration of immunity conferred by aP vaccines relative to the wP vaccines they replaced. A reduced reactogenicity whole-cell pertussis (RRwP) vaccine was recently developed with the goal of achieving the same protection as conferred by wP vaccination but with an improved safety profile, which may benefit countries in which wP vaccines are still in routine use. In this study, we tested the RRwP vaccine in a baboon model of pertussis infection. We found that the RRwP vaccine induced comparable cellular and humoral immune responses and comparable protection following challenge relative to the wP vaccine, while significantly reducing injection-site reactogenicity.IMPORTANCEThe World Health Organization (WHO) recommended in 2015 that countries administering wP vaccines in their national vaccine programs should continue to do so, and that switching to aP vaccines for primary infant immunization should only be considered if periodic booster vaccinations and/or maternal immunization could be assured and sustained in their national immunization schedules (WHO, Vaccine 34:1423-1425, 2016, https://doi.org/10.1016/j.vaccine.2015.10.136). Due to the considerably higher cost of aP vaccines and the larger number of doses required, most LMICs continue to use wP vaccines. The development and introduction of a wP vaccine that induces fewer adverse events without sacrificing protection would significantly benefit countries in which wP vaccines are still in routine use. The results of this study indicate this desirable goal may be achievable.

• Klíčová slova
• baboon model, pertussis, whole cell vaccines,
• MeSH
• Bordetella pertussis imunologie   MeSH
• modely nemocí na zvířatech MeSH
• Papio * imunologie   MeSH
• pertuse * prevence a kontrola   imunologie   MeSH
• pertusová vakcína * imunologie   aplikace a dávkování   MeSH
• protilátky bakteriální krev   MeSH
• vakcinace MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• pertusová vakcína * MeSH
• protilátky bakteriální MeSH