Question:How do acellular vaccines compare with whole-cell pertussis vaccines for preventing whooping cough in children?

Clinical Answer:

Randomized controlled trials with a total of around 100,000 infants show that a 5-component acellular vaccine and a whole cell vaccine have similar effectiveness for preventing whooping cough. However, infants vaccinated with the 3-component acellular vaccine have a higher incidence of whooping cough than those vaccinated with the whole cell vaccine.

Major adverse effects such as hypotonia or hyporesponsiveness, encephalopathy and confusion and minor adverse effects like anorexia, drowsiness, fever, irritability, prolonged crying, vomiting, injection site pain, swelling, redness and induration are less common with the acellular vaccine than the whole cell vaccine.

The lower reactogenicity of the acellular vaccine makes it a better option in countries where vaccine uptake depends on parental consent. In countries where the risk of pertussis infection and severe disease is higher, the higher efficacy of the whole cell vaccine is a better choice than the 3-component acellular vaccine.

Full outcome data is detailed below:

1.Acellular vaccine versus whole-cell pertussis vaccines

  • Population, Intervention, Comparator

    Population:

    Children aged six weeks to four months (five trials assessing efficacy) or children aged six weeks to six years (52 trials assessing adverse effects). Most studies excluded infants with a history of pertussis, neurological disorders, and/or cardiac failure. No further population details were provided.

    Most vaccines were given in three doses, with some studies administering a fourth; the timing of doses varied across studies

    Intervention:

    Acellular vaccine: purified, detoxified pertussis antigens (aP) vaccine or diphtheria-tetanus-aP vaccine

    Comparator:

    Whole-cell pertussis vaccine: killed whole B. pertussis organisms (wP) vaccine, diphtheria-tetanus-wP vaccine, or diphtheria-tetanus toxoid vaccine

  • OUTCOME 1.1: Incidence of whooping cough (21 or more consecutive days of paroxysmal cough with confirmation of B. pertussis infection by culture, appropriate serology or contact with a household member who has culture-confirmed pertussis)

    Risk of bias of studies:

    The reviewers did not perform a GRADE assessment of the quality of the evidence. Of five studies, all had unclear numbers of withdrawals, two (40%) failed to reported adequate concealment of allocation and one (20%) random sequence generation, and two (40%) failed to report blinding of outcome assessors.

    Narrative result:

    Five studies with 101,825 infants reported that overall, there was no statistically significant difference between a five-component acellular vaccine compared with a whole-cell vaccine; however, the incidence of whooping cough was higher with a three-component vaccine compared with a whole-cell vaccine. There was no statistically significant difference between the three-component and five-component acellular vaccines.

    Relative effect or mean difference:

    The studies were not meta-analyzed, therefore results are presented in a narrative only.

    Reference:
    Zhang L, Prietsch SOM, Axelsson I, Halperin SA. Acellular vaccines for preventing whooping cough in children. Cochrane Database of Systematic Reviews ��2014, Issue 9. Art. No.: CD001478. DOI: 10.1002/14651858.CD001478.pub6. [Review search date: January 2014]
    • OUTCOME 1.2: Incidence of pertussis disease (seven or more consecutive days of cough with confirmation of B. pertussis infection by culture or appropriate serology)

      Risk of bias of studies:

      The reviewers did not perform a GRADE assessment of the quality of the evidence. The trial was at an unclear risk of bias for all criteria assessed.

      Narrative result:

      One study with 3,619 infants showed that the diphtheria-tetanus-aP acelllular vaccine had a higher incidence of pertussis disease than the diphtheria-tetanus-wP vaccine.

      Reference:
      Zhang L, Prietsch SOM, Axelsson I, Halperin SA. Acellular vaccines for preventing whooping cough in children. Cochrane Database of Systematic Reviews ��2014, Issue 9. Art. No.: CD001478. DOI: 10.1002/14651858.CD001478.pub6. [Review search date: January 2014]
      • OUTCOME 1.3: Infection-related mortality during or after the primary dose series

        Risk of bias of studies:

        The reviewers did not perform a GRADE assessment of the quality of the evidence. Of 13 studies, all had unclear numbers of withdrawals, ten (77%) failed to reported adequate allocation concealment and/or random sequence generation processes, and seven (54%) failed to report blinding of outcome assessors.

        Narrative result:

        13 studies with 34,498 infants found no statistically significant difference between groups.

        Relative effect or mean difference:

        There was no statistically significant difference between groups (RR 0.97, 95% CI 0.23 to 4.16).

        Forest plot from Cochrane Review

        Absolute effect:

        There was no statistically significant difference between groups.

        Reference:
        Zhang L, Prietsch SOM, Axelsson I, Halperin SA. Acellular vaccines for preventing whooping cough in children. Cochrane Database of Systematic Reviews ��2014, Issue 9. Art. No.: CD001478. DOI: 10.1002/14651858.CD001478.pub6. [Review search date: January 2014]
        • OUTCOME 1.4: Encephalopathy during or after the primary dose series

          Risk of bias of studies:

          The reviewers did not perform a GRADE assessment of the quality of the evidence. Of nine studies, all had unclear numbers of withdrawals, five (56%) failed to reported adequate allocation concealment and/or random sequence generation processes, and four (44%) failed to report blinding of outcome assessors.

          Narrative result:

          Nine studies with 113,762 infants reported no incidences of encephalopathy.

          Relative effect or mean difference:

          There were no incidences of encephalopathy reported.

          Reference:
          Zhang L, Prietsch SOM, Axelsson I, Halperin SA. Acellular vaccines for preventing whooping cough in children. Cochrane Database of Systematic Reviews ��2014, Issue 9. Art. No.: CD001478. DOI: 10.1002/14651858.CD001478.pub6. [Review search date: January 2014]
          • OUTCOME 1.5: Convulsions

            Narrative result:

            The incidence of convulsions was analyzed according to whether the infant was receiving the primary series of injections or a booster.

            Reference:
            Zhang L, Prietsch SOM, Axelsson I, Halperin SA. Acellular vaccines for preventing whooping cough in children. Cochrane Database of Systematic Reviews ��2014, Issue 9. Art. No.: CD001478. DOI: 10.1002/14651858.CD001478.pub6. [Review search date: January 2014]
            • Subgroup analysis 1.5.1: Convulsions - [subgroup: Primary dose series]
              Risk of bias of studies:

              The reviewers did not perform a GRADE assessment of the quality of the evidence. Of 15 studies, all had unclear numbers of withdrawals, ten (66%) failed to reported adequate allocation concealment and/or one random sequence generation processes, and eight (40%) failed to report blinding of outcome assessors.

              Narrative result:

              15 studies with 124,387 infants found that acellular vaccine had a lower incidence of convulsions compared with whole-cell vaccine.

              Relative effect or mean difference:

              There was a statistically significant difference between groups, in favor of acellular (RR 0.47, 95% CI 0.31 to 0.73).

              Forest plot from Cochrane Review

              Absolute effect:

              We could not calculate absolute results for this outcome because of low event rates.

              Reference:
              Zhang L, Prietsch SOM, Axelsson I, Halperin SA. Acellular vaccines for preventing whooping cough in children. Cochrane Database of Systematic Reviews ��2014, Issue 9. Art. No.: CD001478. DOI: 10.1002/14651858.CD001478.pub6. [Review search date: January 2014]
            • Subgroup analysis 1.5.2: Convulsions - [subgroup: Booster dose]
              Risk of bias of studies:

              The reviewers did not perform a GRADE assessment of the quality of the evidence. Of 11 studies, all had unclear numbers of withdrawals, nine (82%) failed to reported adequate allocation concealment and/or one random sequence generation processes, and ten (91%) failed to report blinding of outcome assessors.

              Narrative result:

              11 studies with 2,647 infants found no statistically significant difference between groups.

              Relative effect or mean difference:

              There was no statistically significant difference between groups (RR 0.46, 95% CI 0.02 to 11.20).

              Forest plot from Cochrane Review

              Absolute effect:

              There was no statistically significant difference between groups.

              Reference:
              Zhang L, Prietsch SOM, Axelsson I, Halperin SA. Acellular vaccines for preventing whooping cough in children. Cochrane Database of Systematic Reviews ��2014, Issue 9. Art. No.: CD001478. DOI: 10.1002/14651858.CD001478.pub6. [Review search date: January 2014]
          • OUTCOME 1.6: Hypotonic/hyporesponsive episodes

            Narrative result:

            The incidence of hypotonic/hyporesponsive episodes was analyzed according to whether the infant was receiving the primary series of injections or a booster.

            Reference:
            Zhang L, Prietsch SOM, Axelsson I, Halperin SA. Acellular vaccines for preventing whooping cough in children. Cochrane Database of Systematic Reviews ��2014, Issue 9. Art. No.: CD001478. DOI: 10.1002/14651858.CD001478.pub6. [Review search date: January 2014]
            • Subgroup analysis 1.6.1: Hypotonic/hyporesponsive episodes - [subgroup: Primary dose series]
              Risk of bias of studies:

              The reviewers did not perform a GRADE assessment of the quality of the evidence. Of 11 studies, all had unclear numbers of withdrawals, seven (64%) failed to reported adequate allocation concealment and/or one random sequence generation processes, and five (45%) failed to report blinding of outcome assessors.

              Narrative result:

              11 studies with 121,573 infants found that acellular vaccine had a lower incidence of hypotonic/hyporesponsive episodes compared with whole-cell vaccine.

              Relative effect or mean difference:

              There was a statistically significant difference between groups, in favor of acellular (RR 0.26, 95% CI 0.08 to 0.81).

              Forest plot from Cochrane Review

              Absolute effect:

              We could not calculate absolute results for this outcome because of low event rates.

              Reference:
              Zhang L, Prietsch SOM, Axelsson I, Halperin SA. Acellular vaccines for preventing whooping cough in children. Cochrane Database of Systematic Reviews ��2014, Issue 9. Art. No.: CD001478. DOI: 10.1002/14651858.CD001478.pub6. [Review search date: January 2014]
            • Subgroup analysis 1.6.2: Hypotonic/hyporesponsive episodes - [subgroup: Booster dose]
              Risk of bias of studies:

              The reviewers did not perform a GRADE assessment of the quality of the evidence. Of seven studies, all had unclear numbers of withdrawals, six (86%) failed to reported adequate allocation concealment and/or one random sequence generation processes, and six (86%) failed to report blinding of outcome assessors.

              Narrative result:

              Seven studies with 2,487 infants reported no incidences of hypotonic/hyporesponsive episodes.

              Relative effect or mean difference:

              There were no incidences of hypotonic/hyporesponsive episodes.

              Reference:
              Zhang L, Prietsch SOM, Axelsson I, Halperin SA. Acellular vaccines for preventing whooping cough in children. Cochrane Database of Systematic Reviews ��2014, Issue 9. Art. No.: CD001478. DOI: 10.1002/14651858.CD001478.pub6. [Review search date: January 2014]
          • OUTCOME 1.7: Non-completion of scheduled doses due to adverse events

            Risk of bias of studies:

            The reviewers did not perform a GRADE assessment of the quality of the evidence. Of 14 studies, all had unclear numbers of withdrawals, eight (57%) failed to reported adequate allocation concealment and/or one random sequence generation processes, and six (43%) failed to report blinding of outcome assessors.

            Narrative result:

            14 studies with 108,909 infants found that there was a lower rate of non-completion of the primary series due to adverse events with acellular vaccines compared with whole-cell vaccine.

            Relative effect or mean difference:

            There was a statistically significant difference between groups, in favor of acellular (RR 0.23, 95% CI 0.12 to 0.43).

            Forest plot from Cochrane Review

            Absolute effect:

            We could not calculate absolute results for this outcome because of low event rates.

            Reference:
            Zhang L, Prietsch SOM, Axelsson I, Halperin SA. Acellular vaccines for preventing whooping cough in children. Cochrane Database of Systematic Reviews ��2014, Issue 9. Art. No.: CD001478. DOI: 10.1002/14651858.CD001478.pub6. [Review search date: January 2014]
            • OUTCOME 1.8: Minor adverse events during or after the primary series of doses

              Risk of bias of studies:

              Most of the 52 safety trials did not describe the methods for random sequence generation and allocation concealment. Although the reports stated double blinding, details about the methods, and who the blinding referred to, were generally unclear. The review stated that with the exception of one study, follow-up was balanced across the vaccine groups and covered over 90% of available infants at each vaccine dose, however, all studies were classified as having an unclear risk of attrition bias.

              Narrative result:

              Between six (with 16,347 infants) and 19 studies (with 23,267 infants) evaluated a large number of minor adverse events. On the whole, minor adverse events were less common with acellular vaccine compared with whole-cell vaccines. Lower incidences were observed for anorexia, fever, irritability/fretfulness, prolonged crying, pain/tenderness, redness, swelling/induration for all three primary series doses, drowsiness for doses 2 and 3, and vomiting for doses 1 and 2.

              Relative effect or mean difference:

              A large number of meta-analyses and subgroup analyses were performed; results are presented in a narrative only.

              Reference:
              Zhang L, Prietsch SOM, Axelsson I, Halperin SA. Acellular vaccines for preventing whooping cough in children. Cochrane Database of Systematic Reviews ��2014, Issue 9. Art. No.: CD001478. DOI: 10.1002/14651858.CD001478.pub6. [Review search date: January 2014]

              2.Acellular vaccine versus placebo/DT

              • Population, Intervention, Comparator

                Population:

                Children aged six weeks to four months (six trials assessing efficacy) or children aged six weeks to six years (number of trials assessing adverse effects for this comparison unclear; 52 trials in total). Most studies excluded infants with a history of pertussis, neurological disorders, and/or cardiac failure. No further population details were provided.

                Intervention:

                Acellular vaccine: purified, detoxified pertussis antigens (aP) vaccine or diphtheria-tetanus-aP vaccine. Most vaccines were given in three doses, with some studies administering a fourth; the timing of doses varied across studies

                Comparator:

                Placebo or diphtheria-tetanus toxoid vaccine

              • OUTCOME 2.1: Incidence of whooping cough (21 or more consecutive days of paroxysmal cough with confirmation of B. pertussis infection by culture, appropriate serology or contact with a household member who has culture-confirmed pertussis)

                Risk of bias of studies:

                The reviewers did not perform a GRADE assessment of the quality of the evidence. Of six studies, all had unclear numbers of withdrawals, two (33%) failed to reported adequate concealment of allocation and one (11%) random sequence generation, and three (50%) failed to report blinding of outcome assessors.

                Narrative result:

                Six studies with 32,356 infants, plus a substudy of 1,847 infants compared with an unknown number of unvaccinated infants, reported varying absolute efficacy rates. Reported efficacy rates were: Amvax 71%; JNIH6 78%; JNIH7 78%; SKB 59% and 84%; Chiron-Biocine 84%; Connaught 85%; Diphtheria-tetanus-aP 79% and 85%; Connaught(W) 36% and 48%; and Diphtheria-tetanus-wP 84% and 96%.

                Relative effect or mean difference:

                The studies were not meta-analyzed, therefore results are presented in a narrative only.

                Reference:
                Zhang L, Prietsch SOM, Axelsson I, Halperin SA. Acellular vaccines for preventing whooping cough in children. Cochrane Database of Systematic Reviews ��2014, Issue 9. Art. No.: CD001478. DOI: 10.1002/14651858.CD001478.pub6. [Review search date: January 2014]
                • OUTCOME 2.2: Incidence of pertussis disease (seven or more consecutive days of cough with confirmation of B. pertussis infection by culture or appropriate serology)

                  Risk of bias of studies:

                  The reviewers did not perform a GRADE assessment of the quality of the evidence. Of five studies, all had unclear numbers of withdrawals, two (40%) failed to reported adequate concealment of allocation and/or random sequence generation, and two (40%) failed to report blinding of outcome assessors.

                  Narrative result:

                  Five studies with 32,356 infants reported varying absolute efficacy rates. Reported efficacy rates were: Amvax 54%; JNIH6 58%; JNIH7 41%; SKB 44% and 71%; Chiron-Biocine 71%; Connaught 78%; Diphtheria-tetanus-aP 72%; Connaught(W) 23% and 42%; and Diphtheria-tetanus-wP 83%.

                  Relative effect or mean difference:

                  The studies were not meta-analyzed, therefore results are presented in a narrative only.

                  Reference:
                  Zhang L, Prietsch SOM, Axelsson I, Halperin SA. Acellular vaccines for preventing whooping cough in children. Cochrane Database of Systematic Reviews ��2014, Issue 9. Art. No.: CD001478. DOI: 10.1002/14651858.CD001478.pub6. [Review search date: January 2014]
                  • OUTCOME 2.3: Infection-related mortality

                    Risk of bias of studies:

                    The reviewers did not perform a GRADE assessment of the quality of the evidence. Of four studies, all reported using adequate allocation concealment and blinding of outcome assessors, but all had unclear numbers of withdrawals and one (25%) failed to report the use of adequate random sequence generation.

                    Narrative result:

                    Four studies with 25,902 infants found no statistically significant difference between groups.

                    Relative effect or mean difference:

                    There was no statistically significant difference between groups (RR 1.21, 95% CI 0.19 to 7.80).

                    Forest plot from Cochrane Review

                    Absolute effect:

                    There was no statistically significant difference between groups.

                    Reference:
                    Zhang L, Prietsch SOM, Axelsson I, Halperin SA. Acellular vaccines for preventing whooping cough in children. Cochrane Database of Systematic Reviews ��2014, Issue 9. Art. No.: CD001478. DOI: 10.1002/14651858.CD001478.pub6. [Review search date: January 2014]
                    • OUTCOME 2.4: Encephalopathy after the primary series of doses

                      Risk of bias of studies:

                      The reviewers did not perform a GRADE assessment of the quality of the evidence. Both studies reported using adequate allocation concealment and blinding of outcome assessors, but both had unclear numbers of withdrawals and one (50%) failed to report the use of adequate random sequence generation.

                      Narrative result:

                      Two studies with 18,650 infants reported no incidences of encephalopathy.

                      Relative effect or mean difference:

                      There were no incidences of encephalopathy.

                      Reference:
                      Zhang L, Prietsch SOM, Axelsson I, Halperin SA. Acellular vaccines for preventing whooping cough in children. Cochrane Database of Systematic Reviews ��2014, Issue 9. Art. No.: CD001478. DOI: 10.1002/14651858.CD001478.pub6. [Review search date: January 2014]
                      • OUTCOME 2.5: Convulsions after the primary series of doses

                        Risk of bias of studies:

                        The reviewers did not perform a GRADE assessment of the quality of the evidence. Of four studies, all reported using adequate allocation concealment and blinding of outcome assessors, but all had unclear numbers of withdrawals and one (25%) failed to report the use of adequate random sequence generation.

                        Narrative result:

                        Four studies with 25,901 infants found no statistically significant difference between groups.

                        Relative effect or mean difference:

                        There was no statistically significant difference between groups (RR 0.44, 95% CI 0.12 to 1.69).

                        Forest plot from Cochrane Review

                        Absolute effect:

                        There was no statistically significant difference between groups.

                        Reference:
                        Zhang L, Prietsch SOM, Axelsson I, Halperin SA. Acellular vaccines for preventing whooping cough in children. Cochrane Database of Systematic Reviews ��2014, Issue 9. Art. No.: CD001478. DOI: 10.1002/14651858.CD001478.pub6. [Review search date: January 2014]
                        • OUTCOME 2.6: Hypotonic/hyporesponsive episodes after the primary series of doses

                          Risk of bias of studies:

                          The reviewers did not perform a GRADE assessment of the quality of the evidence. Of four studies, all reported using adequate allocation concealment and blinding of outcome assessors, but all had unclear numbers of withdrawals and one (25%) failed to report the use of adequate random sequence generation.

                          Narrative result:

                          Four studies with 25,901 infants found no statistically significant difference between groups.

                          Relative effect or mean difference:

                          There was no statistically significant difference between groups (RR 0.29, 95% CI 0.02 to 5.13).

                          Forest plot from Cochrane Review

                          Absolute effect:

                          There was no statistically significant difference between groups.

                          Reference:
                          Zhang L, Prietsch SOM, Axelsson I, Halperin SA. Acellular vaccines for preventing whooping cough in children. Cochrane Database of Systematic Reviews ��2014, Issue 9. Art. No.: CD001478. DOI: 10.1002/14651858.CD001478.pub6. [Review search date: January 2014]
                          • OUTCOME 2.7: Non-completion of scheduled doses due to adverse events

                            Risk of bias of studies:

                            The reviewers did not perform a GRADE assessment of the quality of the evidence. Of four studies, all reported using adequate allocation concealment and blinding of outcome assessors, but all had unclear numbers of withdrawals and one (25%) failed to report the use of adequate random sequence generation.

                            Narrative result:

                            Four studies with 25,901 infants found no statistically significant difference between groups.

                            Relative effect or mean difference:

                            There was no statistically significant difference between groups (RR 0.70, 95% CI 0.38 to 1.29).

                            Forest plot from Cochrane Review

                            Absolute effect:

                            There was no statistically significant difference between groups.

                            Reference:
                            Zhang L, Prietsch SOM, Axelsson I, Halperin SA. Acellular vaccines for preventing whooping cough in children. Cochrane Database of Systematic Reviews ��2014, Issue 9. Art. No.: CD001478. DOI: 10.1002/14651858.CD001478.pub6. [Review search date: January 2014]
                            • OUTCOME 2.8: Minor adverse events during or after the primary series of doses

                              Risk of bias of studies:

                              The reviewers did not perform a GRADE assessment of the quality of the evidence. Most of the 52 safety trials did not describe the methods for random sequence generation and allocation concealment. Although the reports stated double blinding, details about the methods, and who the blinding referred to, were generally unclear. The review stated that with the exception of one study, follow-up was balanced across the vaccine groups and covered over 90% of available infants at each vaccine dose, however, all studies were classified as having an unclear risk of attrition bias.

                              Narrative result:

                              Between one (with 3,535 infants) and three studies (with 11,255 infants) evaluated a large number of minor adverse events. There were no statistically significant differences in the incidence of minor adverse events (anorexia, fever, irritability/fretfulness, prolonged crying, pain/tenderness, redness, swelling/induration for all three primary series doses, drowsiness, vomiting) between groups; several of the analyses may have been underpowered to detect clinically significant differences.

                              Relative effect or mean difference:

                              A large number of meta-analyses and subgroup analyses were performed; results are presented in a narrative only.

                              Reference:
                              Zhang L, Prietsch SOM, Axelsson I, Halperin SA. Acellular vaccines for preventing whooping cough in children. Cochrane Database of Systematic Reviews ��2014, Issue 9. Art. No.: CD001478. DOI: 10.1002/14651858.CD001478.pub6. [Review search date: January 2014]

                              Additional Information:

                              DOI

                              10.1002/cca.392

                              Publication Dates

                              1. Published Online: 16 JUL 2014

                              CCA derived from

                              Zhang L, Prietsch SOM, Axelsson I, Halperin SA. Acellular vaccines for preventing whooping cough in children. Cochrane Database of Systematic Reviews ��2014, Issue 9. Art. No.: CD001478. DOI: 10.1002/14651858.CD001478.pub6. [Review search date: January 2014]

                              How to Cite

                              How do acellular vaccines compare with whole-cell pertussis vaccines for preventing whooping cough in children? Smitha Bhat (MD, MRCP (UK)) (on behalf of Cochrane Clinical Answers Editors). Cochrane Clinical Answers 2012. DOI: 10.1002/cca.392.

                              Further Information

                              • CCA Associate editor: Smitha Bhat (MD, MRCP (UK)), Professor, Father Muller Medical College, Mangalore, Karnataka, India.
                              • CCA Editor: Karen Pettersen. Correspondence to kpettersen@wiley.com.