Hexavalent Vaccines in Preterm Infants: What Real-World and Clinical Data Reveal
In this article
Infection Risk and Vaccination Challenges in Preterm Infants
Preterm birth and low birth weight remain major contributors to infant morbidity and mortality worldwide. In 2020, an estimated 13.4 million infants — about one in ten live births — were born preterm (<37 weeks’ gestation), with nearly one million deaths attributed to complications of prematurity.1 Between 2010 and 2020, approximately 152 million infants were born preterm, with little change in global rates.¹ Prematurity is now the leading cause of death among children under five years, accounting for more than one in five deaths in this age group.1
Infants born prematurely or with low birth weight (LBW, ˂2500 g) are particularly vulnerable to infection due to immaturity of innate and adaptive immune responses, including impaired pathogen recognition, reduced complement activity, and diminished neutrophil and monocyte function.2 In addition, the transplacental transfer of maternal immunoglobulin G (IgG), a key source of early-life protection, occurs predominantly during the third trimester, resulting in lower levels of maternally derived antibodies in preterm infants.2,3 Maternal IgG is transported across the placenta via neonatal Fc-receptor (FcRn) mediated mechanisms, but because most transfer occurs late in gestation, preterm infants generally have lower antigen-specific IgG levels at birth.2,3
This immunological vulnerability increases susceptibility to vaccine-preventable infections like pertussis, invasive pneumococcal disease, and Haemophilus influenzae type b infection.2 Although vaccination in preterm infants may sometimes be delayed due to clinical concerns, guidelines recommend routine immunization according to chronological age and scheduled doses to ensure timely protection.2 Combination vaccines can facilitate adherence to immunization schedules by reducing the number of injections. Hexavalent vaccines combining diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus, and Haemophilus influenzae type b antigens are therefore an important component of infant immunization programs and have been evaluated for their immunogenicity and safety in preterm and LBW infants.2
Clinical Evidence on Hexavalent Vaccination in Preterm and Low Birth Weight Infants
Evidence base
A review evaluating the hexavalent diphtheria–tetanus–acellular pertussis–hepatitis B–inactivated poliovirus–Haemophilus influenzae type b vaccine (DTPa-HBV-IPV/Hib) summarized data from 10 clinical studies and 15 years of post-marketing safety surveillance in infants with a history of prematurity or LBW.2
- >1600 preterm infants
- Infants with gestational age as early as 24 weeks evaluated
- Vaccine administered alone or co-administered with routine pediatric vaccines
Immunogenicity outcomes
Primary vaccination (3-dose series)2
Seroprotection rates:
- ≥98.7% seropositive for diphtheria and tetanus
- 100% for poliovirus types 1 and 2
- 100% for poliovirus type 3 in most cohorts; 90.9% in infants born at 27–31 weeks’ gestation
- ≥92.4% vaccine response to pertussis antigens
Hib responses:
- ≥92.5% seropositivity for antibodies against polyribosylribitol phosphate
- Geometric mean antibody titers correlated with gestational age and birth weight
- Lower antibody concentrations observed in infants with very low birth weight (˂1500 g)
Booster responses2
Booster doses produced marked increases in antibody concentrations, indicating effective immune priming.
- 100% seroprotection for diphtheria and tetanus after booster
- Robust increases in polio and Hib antibody titers
- High antibody levels maintained through preschool age in follow-up studies.
Cell-Mediated Immunity2
In one study, pertussis-specific cell-mediated immunity was demonstrated in preterm infants (<31 weeks’ gestation), with detectable T-cell responses to pertussis antigens, showing immune responses comparable to those in term infants and a T helper type-2 (Th2)–biased pattern typical of early life immunity.
Co-administration with other vaccines2
The hexavalent vaccine was safely co-administered with routine pediatric vaccines such as pneumococcal conjugate, rotavirus, and meningococcal vaccines, as well as respiratory syncytial virus immunoglobulin, without compromising immune responses to hexavalent vaccine antigens.
Safety and Reactogenicity
The clinical studies indicate that the DTPa-HBV-IPV/Hib vaccine is generally well tolerated in preterm and low birth weight infants. The occurrence and intensity of solicited local and general symptoms such as fever, drowsiness, and irritability after primary vaccination were similar in preterm and term infants and were not influenced by birth weight. Overall safety following primary and booster vaccination in preterm infants was comparable to that observed in term infants, with the exception of cardiorespiratory events.2
Cardiorespiratory Events After Vaccination
Cardiorespiratory events such as apnea, bradycardia, and oxygen desaturation have been reported in preterm infants following vaccination. In these clinical studies, 13–30% of medically stable preterm infants experienced apnea and/or bradycardia after receiving the vaccine, most commonly after the first dose.2 Episodes were generally transient and resolved spontaneously or with minimal intervention (e.g., supplemental oxygen or tactile stimulation). The risk appears to be influenced primarily by underlying neonatal conditions, and 48–72-hour monitoring may be considered in very premature infants.2
Post-Marketing Safety Surveillance
Additional safety data from 15 years of post-marketing surveillance further support the vaccine’s safety profile in preterm infants. Since launch until 01 September 2015, 421 adverse event cases were reported in infants with a history of prematurity. The most frequently reported events included pyrexia, crying, apnea, cyanosis, and bradycardia.2
Conclusion
Evidence from clinical trials and long-term surveillance indicates that the hexavalent DTPa-HBV-IPV/Hib vaccine provides strong immunogenicity and an acceptable safety profile in preterm and low birth weight infants. High seroprotection rates after primary and booster vaccination support effective immune protection in this population. Although transient cardiorespiratory events may occur in very premature infants, they are generally self-limited. Overall, current evidence supports vaccination according to chronological age to ensure timely protection against multiple vaccine-preventable diseases in this vulnerable group.
References
- United Nations Children’s Fund (UNICEF). 150 million babies born preterm in the last decade. Published May 10, 2023. Accessed March 13, 2026. https://www.unicef.org/press-releases/150-million-babies-born-preterm-last-decade
- Omeñaca F, Vázquez L, Garcia-Corbeira P, et al. Immunization of preterm infants with GSK's hexavalent combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus-Haemophilus influenzae type b conjugate vaccine: A review of safety and immunogenicity. Vaccine. 2018;36(7):986-996. doi: 10.1016/j.vaccine.2018.01.005
- Fouda GG, Martinez DR, Swamy GK, Permar SR. The Impact of IgG transplacental transfer on early life immunity. Immunohorizons. 2018;2(1):14-25. doi:10.4049/immunohorizons.1700057
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).
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).