Reactogenicity After Primary Hexavalent Vaccination: Local vs Systemic—What Meta-Analyses Show
In this article
Summary
Key points
- Pooled analysis of 6 randomized controlled trials provides a robust and generalizable assessment of hexavalent vaccine reactogenicity
- DT3aP-based hexavalent vaccine is associated with a statistically significant reduction in injection-site reactions (pain, erythema, swelling) compared to DT2aP
- Incidence of fever and irritability is consistently lower with the DT3aP formulation, indicating improved systemic tolerability
- Drowsiness and persistent crying occur less frequently with DT3aP, reflecting better post-vaccination comfort in infants
- Vomiting rates are comparable between DT3aP and DT2aP formulations, suggesting no additional systemic safety trade-off
- Grade 3 and serious adverse events remain rare across both groups, with no established causal relationship to vaccination
- Both hexavalent vaccines demonstrate an overall favorable and clinically acceptable safety profile for routine primary immunization
Introduction
The expanding number of vaccine-preventable diseases included in infant immunization programs has made vaccination schedules increasingly complex during early childhood. Combination vaccines were developed to address this challenge by incorporating multiple antigens into a single formulation, enabling protection against several infections while reducing the number of injections required during routine visits.1,2 Accordingly, the Advisory Committee on Immunization Practices (ACIP) recommends the use of combination vaccines as an effective strategy to simplify vaccine administration and reduce barriers associated with multiple injections and complex dosing schedules.3 These vaccines have been used in pediatric immunization programs for decades, beginning with the diphtheria–tetanus–pertussis (DTP) vaccine, and have progressively expanded to include additional antigens within a single product.2
Hexavalent vaccines represent a further advancement in combination vaccine technology, providing protection against diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B, and Haemophilus influenzae type b (Hib) in a single injection.2,4 Since their introduction in Europe in 2000, these vaccines have been widely incorporated into routine infant immunization schedules.2 Despite the well-established benefits of vaccination, parental concerns about vaccine safety, particularly beliefs that vaccines may cause adverse effects or be unsafe, have been consistently associated with lower vaccination uptake and are among the most frequently cited reasons for vaccine hesitancy.5,6 In this context, short-term local and systemic reactions following vaccination, collectively referred to as reactogenicity, represent a key component of vaccine safety evaluation.4 A systematic review and meta-analysis of randomized controlled trials therefore assessed solicited local and systemic reactions following primary hexavalent vaccination in infants.5
Evidence Base for the Meta-analysis
The search identified 317 unique records, of which nine publications reporting randomized controlled trials met the inclusion criteria. Six trials evaluating the primary vaccination series were included in the meta-analysis, directly comparing DT3aP-HBV-IPV-Hib and DT2aP-HBV-IPV-Hib. These studies were conducted across Europe, Asia, and Latin America, primarily using 2, 4, and 6-month immunization schedules, and provided the pooled dataset for comparing reactogenicity profiles between the two hexavalent vaccines.4
Local Reactions: Injection-Site Effects
Solicited local reactions were consistently assessed across the randomized trials included in the meta-analysis. These events primarily included pain, redness, and swelling at the injection site, and were recorded within 7 days following any dose of the primary vaccination series.4
Pooled incidence and odds ratio of solicited local reactions after primary hexavalent vaccination4
Local reaction |
DT3aP-HBV-IPV-Hib (%) |
DT2aP-HBV-IPV-Hib (%) |
Pooled Odds Ratio (95% CI) |
Pain at injection site |
75% |
81% |
0.74 (0.62–0.89), p <0.01 |
Redness |
50% |
57% |
0.72 (0.63–0.83), p <0.001 |
Swelling |
37% |
40% |
0.86 (0.74–0.99), p <0.05 |
Grade 3 local reactions |
12% |
14% |
0.81 (0.64–1.01), p = 0.067 |
GSK has created this table based on data from Mukherjee et al., 20214 |
Injection-site pain was the most commonly reported local reaction, followed by redness and swelling. Overall, these reactions occurred slightly less frequently with DT3aP-HBV-IPV-Hib than with DT2aP-HBV-IPV-Hib, with pooled analysis showing significantly lower odds for pain, redness, and swelling. Severe (grade 3) injection-site reactions were uncommon and did not differ significantly between the two vaccines.4
Systemic Reactions: Fever and Behavioral Symptoms
Systemic reactions reported after primary hexavalent vaccination included fever and behavioral symptoms such as irritability and persistent crying. Across pooled randomized trials, several systemic reactions occurred slightly less frequently with DT3aP-HBV-IPV-Hib compared with DT2aP-HBV-IPV-Hib, while vomiting showed similar incidence between the two vaccines. Severe (grade 3) systemic reactions were uncommon.4
Pooled incidence and odds ratio of systemic reactions after primary hexavalent vaccination4
Systemic reaction |
DT3aP-HBV-IPV-Hib (%) |
DT2aP-HBV-IPV-Hib (%) |
Pooled Odds Ratio (95% CI) |
Fever |
48% |
58% |
0.67 (0.54–0.83), p <0.001 |
Irritability |
80% |
84% |
0.82 (0.69–0.98), p <0.05 |
Persistent crying |
73% |
78% |
0.72 (0.61–0.84), p <0.001 |
Drowsiness |
61% |
65% |
0.82 (0.71–0.94), p <0.01 |
Decreased appetite (anorexia) |
45% |
49% |
0.83 (0.72–0.95), p <0.01 |
Vomiting |
34% |
35% |
0.96 (0.83–1.11) |
Grade 3 systemic reactions |
15% |
19% |
0.71 (0.58–0.88), p <0.01 |
GSK has created this table based on data from Mukherjee et al., 20214 |
Serious and Unsolicited Adverse Events
Unsolicited adverse events reported within 7 and 30 days after vaccination were generally similar between the two vaccine groups and were mostly common childhood conditions, such as respiratory or gastrointestinal infections. Vaccine-related adverse events were uncommon in both groups, occurring in ≤2.3% of infants receiving DT3aP-HBV-IPV-Hib and ≤2.4% of those receiving DT2aP-HBV-IPV-Hib. Serious adverse events were rare in both vaccine groups, with reported incidences ranging from <2.4% to 6.0%, and most events were not considered related to vaccination.4
Conclusion
Evidence from pooled randomized controlled trials indicates that hexavalent vaccines used in infant immunization have generally acceptable safety profiles.4 Both vaccines were associated with expected post-vaccination reactions, including injection-site events and transient systemic symptoms such as fever or irritability.4 The meta-analysis showed statistically significant lower odds of several local and systemic reactions including pain, redness, swelling, fever, irritability, and persistent crying, with DT3aP-HBV-IPV-Hib compared with DT2aP-HBV-IPV-Hib, although most reactions were mild and short-lived.4 Unsolicited adverse events largely reflected common pediatric illnesses, while serious adverse events were rare and generally not considered vaccine-related.4 Overall, these findings support the favorable safety profile of hexavalent vaccines during the primary infant immunization series.4
Key Safety Information7
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 ³38°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
- Zepp F, Schmitt HJ, Cleerbout J, Verstraeten T, Schuerman L, Jacquet JM. Review of 8 years of experience with Infanrix hexa (DTPa-HBV-IPV/Hib hexavalent vaccine). Expert Rev Vaccines. 2009;8(6):663-678. doi:10.1586/erv.09.32
- Obando-Pacheco P, Rivero-Calle I, Gómez-Rial J, Rodríguez-Tenreiro Sánchez C, Martinón-Torres F. New perspectives for hexavalent vaccines. Vaccine. 2018;36(36):5485-5494. doi:10.1016/j.vaccine.2017.06.063
- Kurosky SK, Davis KL, Krishnarajah G. Effect of combination vaccines on completion and compliance of childhood vaccinations in the United States. Hum Vaccin Immunother. 2017;13(11):2494-2502. doi:10.1080/21645515.2017.1362515
- Mukherjee P, Akpo EIH, Kuznetsova A, et al. Hexavalent vaccines in infants: a systematic literature review and meta-analysis of the solicited local and systemic adverse reactions of two hexavalent vaccines. Expert Rev Vaccines. 2021;20(3):319-330. doi:10.1080/14760584.2021.1892493
- Smith LE, Amlôt R, Weinman J, Yiend J, Rubin GJ. A systematic review of factors affecting vaccine uptake in young children. Vaccine. 2017;35(45):6059-6069. doi:10.1016/j.vaccine.2017.09.046
- 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
- Infanrix Hexa, Abbreviated Prescribing Information, Version: IFX-H/API/IN updated on 10 May 2023. https://india-pharma.gsk.com/media/a3hbdio3/infanrixhexa.pdf
GSK is not responsible for the third-party website content
Disclaimer
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 india.pharmacovigilance@gsk.com 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-260004 | DOP: April 2026
For more information, please refer the following link
https://india-pharma.gsk.com/media/a3hbdio3/infanrixhexa.pdf
For Healthcare Professionals Only
Key Safety Information
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
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 india.pharmacovigilance@gsk.com
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 india.pharmacovigilance@gsk.com. ©2026 GSK group of companies or its licensor. For more information, please contact: GlaxoSmithKline Pharmaceuticals Limited, Dr. Annie Besant Road, Worli, Mumbai – 400030 (India).