Avidity of pertussis toxin antibodies following vaccination with genetically versus chemically detoxified pertussis toxin-containing vaccines during pregnancy

Abstract

Background: Both the quantity and quality of circulating anti-pertussis toxin antibodies are important for protection against severe pertussis. We compared the avidity of PT-IgG antibodies in pregnant women and their infants following vaccination during pregnancy with pertussis vaccines containing genetically-detoxified pertussis toxin (PT_gen) or chemically-detoxified PT (PT_chem).

Methods: We analyzed serum samples collected earlier from pregnant women (at delivery) and their infants (at birth and 2 months of age) participating in a clinical trial where pregnant women had been vaccinated during pregnancy with recombinant acellular pertussis vaccine containing 1 µg PT_gen (standalone, ap1_gen, [n=37], or combined to tetanus and diphtheria, Tdap1_gen [n=34]), 2 µg PT_gen (Tdap2_gen, n=35), or 5 µg PT_gen (TdaP5_gen, n=34), or acellular pertussis vaccine containing 8 µg PT_chem (Tdap8_chem, n=35). Avidity was assessed by adding increasing concentrations (0.25, 0.5, 1, 1.5, 2, and 3 M) of NH₄SCN as a bond-breaking agent and measuring PT-IgG levels by ELISA.

Findings: Compared with Tdap8_chem, TdaP5_gen vaccination was associated with significantly higher total absolute avidity (p<0.001) and medium-high to very-high avidity PT-IgG levels (p≤0.02) in mothers at delivery, infants at birth and infants at 2 months of age. Avidity was comparable to Tdap8_chem after vaccination with the low-dose PT_gen formulations (ap1_gen, Tdap1_gen or Tdap2_gen). There were no differences for vaccination during the 2^nd or 3^rd trimester of pregnancy.

Interpretation: Compared with chemically detoxified vaccines, vaccination during pregnancy with recombinant genetically detoxified acellular pertussis vaccine at lower PT concentration provides infants with at least similar or higher quality PT-IgG antibodies. Consequently, recombinant pertussis vaccines may offer comparable or better protection against pertussis.

Keywords: avidity; genetically inactivated; maternal immunization; pertussis; pertussis toxin; recombinant vaccine; vaccination during pregnancy.

Figure 1

PT-IgG total relative avidity index and total absolute avidity in women at delivery, newborns at birth and infants at 2 months of age. The figure shows (A) means and 95% confidence intervals (CI) of PT-IgG total relative avidity (total RAI), and (B) geometric mean concentrations (GMC) and 95% CI of PT-IgG total absolute avidity levels in pregnant women at delivery and their infants at birth and 2 months of age after vaccination during pregnancy with Tdap8_chem (orange; diamond);TdaP5_gen (dark purple; downward triangle); Tdap2_gen (purple; upward triangle); Tdap1_gen (pink; square); or ap1_gen (blue; circle). For each individual recombinant vaccine group responses were compared with responses for Tdap8_chem using an Independent t-test: when significant (p-value ≤ 0.05), the p-value is noted.

Figure 2

PT-IgG fractional absolute avidity (F abs) levels in women at delivery, newborns at birth and infants at 2 months of age. The figure shows geometric mean concentrations (GMC) and 95% confidence intervals (CI) for PT-IgG fractional absolute levels (F abs) with different avidities in (A) pregnant women at delivery, and (B) their infants at birth and (C) 2 months of age after vaccination during pregnancy with Tdap8_chem (orange; diamond); TdaP5_gen (dark purple; downward triangle); Tdap2_gen (purple; upward triangle); Tdap1_gen (pink; square)); or ap1_gen (blue; circle). F abs quantified at 0.25M, 0.5M, 1M, 1.5M, 2M, and 3M of NH₄SCN were classified as low, low-medium, medium, medium-high, high and very-high avidity, respectively. Responses were compared For each individual recombinant vaccine group with responses for Tdap8_chem using an Independent t-test: when significant (p-value ≤ 0.05), the p-value is noted.

Figure 3

Total relative avidity index (Total RAI), total absolute avidity levels, and fractional absolute PT-IgG levels measured in newborns at the time of birth according to vaccination in the 2^nd or 3^rd trimester of pregnancy. The figure shows (A) means and 95% confidence intervals (CI) of PT-IgG total relative avidity (total RAI), (B) geometric mean concentrations (GMC) and 95% CI of PT-IgG total absolute levels, and (C) GMCs and 95% CI of fractional absolute levels (F abs) in infants at the time of birth after vaccination with Tdap8_chem (orange; diamond); TdaP5_gen (dark purple; downward triangle); Tdap2_gen (purple; upward triangle); Tdap1_gen (pink; square); or ap1_gen (blue; circle) during the 2^nd trimester (closed symbols and bars) or 3^rd trimester (open symbols and pattern bars). Only F abs quantified at 1.5M, 2M, and 3M of NH₄SCN and classified as medium-high (MH), high (H) and very-high (VH) avidity, are presented. Responses were compared for vaccination during the 2^nd versus. 3^rd trimester using an Independent t-test, but no statistical differences were found.