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Acellular vs. Whole-Cell Pertussis Vaccines: The Safety–Efficacy Trade-Off

Article For Year 1 Vaccination 5 min read

Authored by GSK Vaxipedia

In this article

Summary

Key points

Pertussis continues to impose a significant global burden, with ~941,582 reported cases in 2024, particularly affecting infants²
Acellular pertussis vaccines demonstrate higher efficacy ~84% (95% CI: 76.5–89.4) after three doses compared to whole-cell vaccines ~36% (95% CI: 14.2–52.1)³
Under stricter case definitions, acellular vaccines achieve ~89–90% (CI: Not Reported) efficacy, with markedly reduced disease risk (RR ~0.25 vs wP (95% CI: 0.17–0.36 vs wP))³
Whole-cell vaccines show wide variability in efficacy (46%–92%) (CI: NR; range across studies), influenced by strain composition and manufacturing differences⁷
Acellular vaccines are associated with lower rates of fever, irritability, and persistent crying, indicating improved tolerability^3,4
Discontinuation due to adverse events is 8–10 times lower with acellular vaccines (14–17 vs 135 cases) compared to whole-cell vaccines³
No vaccine-related anaphylaxis or encephalopathy has been reported in controlled clinical settings for either vaccine types³
Overall, acellular pertussis vaccines offer a more favorable benefit–risk profile, balancing strong efficacy with improved safety^3,4

Introduction

Pertussis, or whooping cough, is a highly contagious acute respiratory disease caused by Bordetella pertussis, characterized by paroxysmal cough, inspiratory whoop, and post-tussive vomiting. Infants younger than one year are disproportionately affected, bearing the highest rates of hospitalization, complications, and mortality.¹ Despite decades of immunization, pertussis persists as a significant global health burden; the World Health Organization reported 941,582 cases worldwide in 2024.²

Two classes of pertussis vaccine are available: whole-cell vaccines (wP), containing killed B. pertussis organisms, and acellular vaccines (aP), containing purified bacterial antigens such as pertussis toxoid, filamentous haemagglutinin, pertactin, and fimbriae.³While both reduce disease burden, they differ substantially in their reactogenicity, immunological profiles, and duration of protection.^3-5,8Neither vaccination nor natural infection confers lifelong immunity, resulting in cyclical epidemic peaks every three to five years.^4,6,7

Comparative Efficacy

The pivotal evidence comparing acellular and whole-cell pertussis vaccines comes from a large double-blind, randomized controlled trial conducted in Italy, which enrolled 15,601 infants across four arms: two three-component acellular formulations, one whole-cell formulation, and a diphtheria–tetanus toxoid control group.³ Under the primary case definition (≥21 days of paroxysmal cough with laboratory confirmation), both acellular formulations demonstrated vaccine efficacy of approximately 84% after three doses (95% CI, 76.5–89.4%), compared with only 36% (95% CI, 14.2–52.1%) for the whole-cell product tested in this trial.³

Across progressively broader case definitions—from ≥7 days of any cough to ≥60 days—the acellular vaccines consistently outperformed the whole-cell comparator. At the most restrictive definition (≥60 days of cough), acellular efficacy reached approximately 89–90%.³ Relative risk analysis further supported this finding, with the incidence of pertussis in the acellular groups approximately one-quarter to that of the whole-cell group (relative risk, 0.25; 95% CI, 0.17–0.36).³

It should be noted that the WHO position paper highlights that whole-cell pertussis vaccines are produced using different Bordetella pertussis strains and manufacturing processes across producers, resulting in heterogeneity in immune responses and variability in reported efficacy across studies (approximately 46%–92%).⁷In this controlled head-to-head comparison, acellular vaccines demonstrated higher efficacy and a more favorable tolerability profile.³

Safety Profile

The favourable safety profile of acellular vaccines is well established and was a primary driver of their development. In the Italian trial, whole-cell vaccination was associated with substantially higher rates of local reactions (injection-site redness, swelling, and pain), systemic symptoms (fever, irritability, and prolonged crying), and severe adverse events including hypotonic–hyporesponsive episodes.³ Withdrawals due to adverse events numbered 135 in the whole-cell group, compared with only 14–17 in the acellular groups, an approximately 8- to 10-fold reduction.³

A systematic review by Patterson et al. confirmed these findings across multiple trials, demonstrating that acellular vaccines are associated with significantly fewer adverse events following immunization compared with whole-cell formulations, encompassing both local and systemic reactions.⁴ No cases of anaphylaxis or vaccine-related encephalopathy were reported in either group in the Italian trial.³ The improved tolerability profile of acellular vaccines should support their acceptability in immunization programs, particularly as vaccine safety concerns are a leading driver of parental hesitancy and are associated with delayed or incomplete vaccination.^3,4,9

Immunological Considerations

The two vaccine types are associated with distinct immune response profiles; however, this distinction is not absolute and may vary with the specific formulation. Evidence for these differences is derived largely from animal studies in baboon models, in which whole-cell vaccines have been shown to induce predominantly Th1/Th17-type responses, whereas acellular vaccines are associated with a more Th2-biased profile.¹⁰These findings should be interpreted in context, as the baboon studies evaluated DTaP formulations without additional antigens such as inactivated poliovirus (IPV), a component of hexavalent vaccines.¹⁰The single-stranded RNA (ssRNA) of IPV has been shown to exert an adjuvant effect via activation of innate immune pathways that include Toll-like receptors TLR7 and TLR8.¹⁰ In a murine model, the addition of a TLR7 agonist to an alum-adjuvanted acellular pertussis vaccine shifted the immune response toward a Th1/Th17 profile, with protective capacity comparable to, or greater than, that observed with whole-cell vaccines.¹⁰Pertussis resurgence observed in some settings following the transition to acellular vaccines reflects a multifactorial epidemiological pattern, including underlying disease dynamics, duration of protection, and effects on transmission.¹⁰Acellular pertussis vaccines support effective programmatic strategies, with adolescent and adult booster doses (Tdap) extending protection across age groups, and maternal immunization during second or third trimester providing passive transplacental immunity to vulnerable neonates.^7,11

Conclusion

The choice between acellular and whole-cell pertussis vaccines reflects a balance between efficacy, safety, and immunological considerations. Evidence indicates that acellular vaccines provide robust protection against clinical disease, along with a more favourable tolerability profile, with fewer local and systemic adverse events.^3,4Differences in immune response profiles between vaccine types have been described. However, these are influenced by vaccine composition and should be interpreted in context, particularly in light of findings from animal models and combination vaccine formulations.¹⁰At the population level, pertussis epidemiology remains dynamic, with cyclical patterns of disease observed despite widespread vaccination.^6,7Taken together, the available evidence supports acellular pertussis vaccines as a well-established option for primary immunization, offering a favourable balance of protection and tolerability in infants and young children.^3,4,12

Key Safety Information¹³

Contraindications:

Hypersensitivity to any active substance or excipient or formaldehyde, neomycin and polymyxin. Hypersensitivity after previous administration of diphtheria, tetanus, pertussis, hepatitis B, polio or Hib vaccines. Encephalopathy of unknown aetiology, occurring within 7 days following previous vaccination with pertussis containing vaccine. Postpone administration in acute severe febrile illness.

Special warnings and precautions:

Carefully consider decision to give further doses if: temperature of ≥40.0°C (<48 hours of vaccination), not due to another identifiable cause; collapse or shock-like state (<48 hours of vaccination); persistent, inconsolable crying lasting ≥3 hours (<48 hours of vaccination); convulsions with or without fever, (<3 days of vaccination). Administer with caution in thrombocytopenia or a bleeding disorder. Do not administer intravascularly or intradermally. Rate of febrile reactions higher when co-administered with pneumococcal conjugate vaccine, or with measles-mumps-rubella-varicella vaccine; reactions mostly moderate (less than or equal to 39°C) and transient. Increased reporting rates of convulsions (with or without fever) and hypotonic hyporesponsive episode (HHE) were observed with concomitant administration of INFANRIX HEXA and Prevenar 13.

Special populations:

HIV infection not a contraindication. Consider potential risk of apnoea and need for respiratory monitoring for 48-72h when administering primary immunisation series to very preterm infants (born ≤28 weeks of gestation) and particularly if history of respiratory immaturity.

Pregnancy and Lactation:

INFANRIX HEXA is not intended for use in adults, adequate human data on use during pregnancy or lactation and adequate animal reproduction studies are not available.

Undesirable effects:

Very Common- Appetite lost, crying abnormal, irritability, restlessness, somnolence, fever ≥38°C, local swelling at the injection site (≤50 mm), pain, redness.

For the use only of a Registered Medical Practitioner or a Hospital or a Laboratory

References

Liru C, Jing W, Jing B, Yu Z, Jian T, Min J. Clinical characteristics of pertussis in infants and risk factors for respiratory support. Ann Med. 2025;57(1):2514943. doi:10.1080/07853890.2025.2514943
World Health Organization. Pertussis reported cases and incidence—global. WHO Immunization Data. Accessed May 13, 2026. https://immunizationdata.who.int/global/wiise-detail-page/pertussis-reported-cases-and-incidence?CODE=Global&YEAR
Greco D, Salmaso S, Mastrantonio P, et al. A controlled trial of two acellular vaccines and one whole-cell vaccine against pertussis. N Engl J Med. 1996;334(6):341-348. doi:10.1056/NEJM199602083340601
Patterson J, Kagina BM, Gold M, Hussey GD, Muloiwa R. Comparison of adverse events following immunisation with acellular and whole-cell pertussis vaccines: a systematic review. Vaccine. 2018;36(40):6007-6016. doi: 10.1016/j.vaccine.2018.08.022
Jefferson T, Rudin M, DiPietrantonj C. Systematic review of the effects of pertussis vaccines in children. Vaccine. 2003;21(17-18):2003-2014. doi:10.1016/S0264-410X(02)00770-3
Clark TA. Changing pertussis epidemiology: everything old is new again. J Infect Dis. 2014;209(7):978-981. doi:10.1093/infdis/jiu001
World Health Organization. Pertussis vaccines: WHO position papers. Pertussis position paper page. Published August 28, 2015. Accessed May 13, 2026.
Higgs R, Higgins SC, Ross PJ, Mills KHG. Immunity to the respiratory pathogen Bordetella pertussis. Mucosal Immunol. 2012;5(5):485-500. doi:10.1038/mi.2012.54
Kerrigan AR, Aitnouri I, Mar J, Altman W. What Barriers Exist in the Minds of Vaccine-Hesitant Parents, and How Can We Address Them?. Fam Med. 2020;52(9):626-630. doi:10.22454/FamMed.2020.432940
Chitkara AJ, Parikh R, Mihalyi A, Kolhapure S. Hexavalent Vaccines in India: Current Status. Indian Pediatr. 2019;56(11):939-950.
Munoz FM, Bond NH, Maccato M, et al. Safety and immunogenicity of tetanus diphtheria and acellular pertussis (Tdap) immunization during pregnancy in mothers and infants: a randomized clinical trial. JAMA. 2014;311(17):1760-1769. doi:10.1001/jama.2014.3633
He X, Pu Y, Li Z, Huan S, Yang Y. The global regulatory landscape for combined vaccines: A comparative case study of registration strategies for diphtheria-tetanus-pertussis-containing vaccines. Vaccine. 2025;54:127017. doi:10.1016/j.vaccine.2025.127017
. Infanrix Hexa, Prescribing Information, Version: IFX-H/PI/IN/2025/01 Updated on 09-Dec-2025. https://india-pharma.gsk.com/media/a3hbdio3/infanrixhexa.pdf

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For the use only of a registered medical practitioner or a hospital or a laboratory. Trademarks are owned by or licensed to the GSK group of companies. Refer to full prescribing information before use. Registered medical practitioners can refer company website http://india-pharma.gsk.com/en-in/products/prescribing-information/ for full Product Information. Please report adverse events with any GSK product to the company at [email protected] ©2026 GSK group of companies or its licensor. For more information, please contact: GlaxoSmithKline Pharmaceuticals Limited, Dr. Annie Besant Road, Worli, Mumbai – 400030 (India).

CL Code: PM-IN-INH-WCNT-260013 | DOP: June2026

For more information, please refer the following link

https://india-pharma.gsk.com/media/a3hbdio3/infanrixhexa.pdf

For Indian Healthcare Professionals Only

Key Safety Information

Contraindications

Special warnings and precautions

Special populations

Pregnancy and Lactation

INFANRIX HEXA is not intended for use in adults, adequate human data on use during pregnancy or lactation and adequate animal reproduction studies are not available.

Undesirable effects

Very Common- Appetite lost, crying abnormal, irritability, restlessness, somnolence, fever ≥38°C, local swelling at the injection site (≤50 mm), pain, redness

For the use only of a Registered Medical Practitioner or a Hospital or a Laboratory

Abbreviated Prescribing information of INFANRIX HEXA [Diphtheria, tetanus, pertussis (acellular component), hepatitis B (rDNA), poliomyelitis (inactivated) and Haemophilus type b conjugate vaccine (adsorbed) Ph. Eur.]

ACTIVE INGREDIENT: Each 0.5 ml dose of reconstituted vaccine contains (i) Diphtheria toxoid ≥ 30 IU, (ii) Tetanus toxoid ≥ 40 IU, (iii) Bordetella pertussis antigens (Pertussis toxoid 25mcg, Filamentous Haemagglutinin 25 mcg, Pertactin 8 mcg), (iv) Hepatitis B surface antigen 10 mcg, (v) Inactivated Poliovirus [type 1 (Mahoney strain) 40 D-antigen unit, type 2 (MEF-1 strain) 8 D-antigen unit, type 3 (Saukett strain) 32 D-antigen unit), (vi) Haemophilus influenzae type b polysaccharide (polyribosylribitol phosphate, PRP) 10 mcg conjugated to tetanus toxoid as carrier protein (approximately 25 mcg).

INDICATION: Primary and booster vaccination of infants against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and disease caused by Haemophilus influenzae type b.

DOSAGE AND ADMINISTRATION: Posology: The primary vaccination schedule should be administered according to official recommendations. Full-term infants or Preterm infants (≥24 weeks gestational age): 3-dose primary vaccination: interval of ≥1 month between primary doses. Booster dose ≥6 months after last priming dose; preferably ≤18 months of age. 2-dose primary vaccination: interval of ≥2 month between primary doses. Booster dose ≥6 months after last priming dose; preferably between 11-13 months of age. Administered according to official recommendations. The Expanded Program on Immunisation schedule (at 6, 10, 14 weeks of age) may only be used if hepatitis B vaccine given at birth. Safety and efficacy not been established in children > 36 months of age. Method of Administration: Deep intramuscular injection, preferably at alternating sites for subsequent injections.

CONTRA-INDICATIONS: Hypersensitivity to any active substance or excipient or formaldehyde, neomycin and polymyxin. Hypersensitivity after previous administration of diphtheria, tetanus, pertussis, hepatitis B, polio or Hib vaccines. Encephalopathy of unknown aetiology, occurring within 7 days following previous vaccination with pertussis containing vaccine. Postpone administration in acute severe febrile illness.

SPECIAL WARNINGS and SPECIAL PRECAUTIONS: Precede vaccination by review of medical history and clinical examination. Protective immune response may not be elicited in all vaccinees. Will not prevent disease caused by pathogens other than Corynebacterium diphtheriae, Clostridium tetani, Bordetella pertussis, hepatitis B virus, poliovirus or Haemophilus influenzae type b. However, Hepatitis D can be expected to be prevent. If any following events have occurred in temporal relation to receipt of pertussis-containing vaccine, carefully considered decision to give further doses of pertussis-containing vaccines: temperature of ≥40.0°C (<48 hours of vaccination), not due to another identifiable cause; collapse or shock-like state (<48 hours of vaccination); persistent, inconsolable crying lasting ≥3 hours (<48 hours of vaccination); convulsions with or without fever, (<3 days of vaccination). Appropriate medical treatment and supervision be available in case of rare anaphylactic event. Carefully weigh risk-benefit of immunising or deferring vaccination in infant or child suffering from new onset or progression of severe neurological disorder. Administered with caution in thrombocytopenia or a bleeding disorder. Do not administer intravascularly or intradermally. History of febrile convulsions, family history of convulsions or Sudden Infant Death Syndrome (SIDS) not a contraindication for use. Vaccinees with history of febrile convulsions should be closely followed up. Rate of febrile reactions higher when co-administered with pneumococcal conjugate vaccine, or with measles-mumps-rubella-varicella vaccine; reactions mostly moderate (less than or equal to 39°C) and transient. Increased reporting rates of convulsions (with or without fever) and hypotonic hyporesponsive episode (HHE) were observed with concomitant administration of INFANRIX HEXA and Prevenar 13. Antipyretic treatment should be initiated according to local treatment guidelines. Special populations: HIV infection not a contraindication. Expected immunological response may not be obtained in immunosuppressed patients. Can be given to preterm infants; however lower immune response been observed for some antigens. Consider potential risk of apnoea and need for respiratory monitoring for 48-72h when administering primary immunisation series to very preterm infants (born ≤28 weeks of gestation) and particularly if history of respiratory immaturity. Benefit of vaccination is high; vaccination should not be withheld or delayed. Interference with laboratory testing: Hib capsular polysaccharide antigen excreted in urine, positive urine test observed within 1-2 weeks. Interaction with other medicinal products and other forms of interaction: INFANRIX HEXA can be given concomitantly with pneumococcal conjugate vaccine (PCV7, PCV10 and PCV13), meningococcal serogroup C conjugate vaccine (CRM197 and TT conjugates), meningococcal serogroups A, C, W-135 and Y conjugate vaccine (TT conjugate), oral rotavirus vaccine and measles-mumps-rubella-varicella (MMRV) vaccine. Pregnancy and Lactation: INFANRIX HEXA is not intended for use in adults, adequate human data on use during pregnancy or lactation and adequate animal reproduction studies are not available.

ADVERSE EFFECTS: The following drug-related adverse reactions were reported in clinical studies (data from more than 16,000 subjects) and during post-marketing surveillance.

Very common (≥1/10): Appetite lost, crying abnormal, irritability, restlessness, somnolence, fever ≥38°C, local swelling at the injection site (≤50 mm), pain, redness.

Common (≥1/100 to <1/10): Nervousness, diarrhoea, vomiting, fever >39.5°C, injection site reactions, including induration, local swelling at the injection site (>50 mm).

Uncommon (≥1/1,000 to <1/100): Upper respiratory tract infection, cough, diffuse swelling of the injected limb, sometimes involving the adjacent joint, fatigue.

Rare (≥1/10,000 to <1/1,000): Lymphadenopathy, thrombocytopenia, anaphylactic reactions, anaphylactoid reactions (including urticaria), allergic reactions (including pruritus), collapse or shock-like state (hypotonic-hyporesponsive episode), bronchitis, apnoea, rash, angioedema, swelling of the entire injected limb, extensive swelling reactions, injection site mass, injection site vesicles.

Very rare (<1/10,000): Appetite lost, Convulsions (with or without fever), dermatitis.

OVERDOSE: No cases of overdose reported.

Version: IFX-H/API/IN updated on 10 May 2023.

Registered medical practitioners can refer company website www.gsk-india.com/product-prescribing-information.aspx for full Product Information.

Please report adverse events with any GSK product to the company at [email protected]

For the use only of a registered medical practitioner or a hospital or a laboratory. Trademarks are owned by or licensed to the GSK group of companies. Refer to full prescribing information before use. Registered medical practitioners can refer company website: india-pharma.gsk.com/en-in/products/prescribing-information/ for Full Product Information. Please report adverse events with any GSK product to the company at [email protected]. ©2026 GSK group of companies or its licensor. For more information, please contact: GlaxoSmithKline Pharmaceuticals Limited, Dr. Annie Besant Road, Worli, Mumbai – 400030 (India).