Pertussis, commonly known as whooping cough, is a highly contagious disease of the upper respiratory tract caused by the gram-negative bacterium Bordetella pertussis. Pertussis infection tends to be mild in adults and adolescents, but infants too young to be protected by vaccination are much more susceptible to severe disease and fatality.Citation1 Prevalence of pertussis is cyclical, with outbreaks occurring every 3–4 y. However, in recent years, excessive cases of pertussis have been seen in several developed countries, despite high vaccine coverage rates. This resurgence of pertussis disease, particularly in the very vulnerable group of infants less than 3 months, is a current major public health concern. In response, several countries including the UK, United States, Australia and Belgium, have introduced maternal vaccination programs aimed to protect the infant through boosting maternal antibody levels and hence increase trans-placental antibody transfer. These programs have been extremely successful in reducing pertussis disease in young infants,Citation2,Citation3 and infants born to vaccinated mothers have elevated PT and FHA antibodies compared with maternal sera.Citation4,Citation5 However, there are concerns that the presence of elevated maternal antibodies could blunt the infant's primary response to pertussis vaccination, as has been previously shown for other vaccines including measles,Citation6 hepatitis ACitation7 and influenza.Citation8
Caboré et al. describe in this issue of Virulence, how maternal Tdap vaccination impacts on the infant's antibody avidity following booster vaccination.Citation9 Avidity is the strength of antibody-antigen binding, and as avidity maturation requires B cell somatic hypermutation and clonal selection, it is a reflection of B cell memory to specific antigens. The samples utilised are from a previously published prospective controlled cohort study, which measured the transfer of vaccine-specific antibodies to infants following maternal Tdap vaccination (Tetanus, Diphtheria, acellular Pertussis; Boostrix®), and the infant's antibody responses following their first 3 doses of pertussis-containing vaccine.Citation10 A subsequent study from this group has also reported infants’ antibody levels before and after their booster dose at 15 months, the routine schedule in Belgium.Citation11 The current study adds additional information regarding the avidity of antibodies from these same subjects, pre- and post- booster. The impact of maternal vaccination on antibody avidity in infants was measured by performing ELISAs for antibody against diphtheria toxin (DT), tetanus toxin (TT) and pertussis antigens (pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin (Prn)) in the presence and absence of 1.5M ammonium thiocyanate (NH4SCN). NH4SCN is a dissociating agent that separates high and low avidity antibodies, and thus the principle of the assay is that by comparing the antibody levels between treated and untreated serum, a Relative Avidity Index (RAI) is generated. The protocol followed in this study is that of Almanzar et alCitation12 and a similar method has been used in several pertussis studies, though sometimes with varying concentration of NH4SCN.Citation13-16 Avidity was measured on samples taken before and one month after the infants’ fourth vaccine dose at 15 months of age. This is the first comparison, to our knowledge, of antibody avidity to a booster dose in infants born to pertussis-vaccinated and unvaccinated pregnancies.
In this current study, samples tested before the booster dose (15 months of age), demonstrated no difference in antibody avidity to any antigens between babies born to vaccinated and unvaccinated mothers. As expected based on previous studies demonstrating that repeated vaccine doses increases antibody avidity,Citation16,Citation17 the booster dose increased avidity in all groups and to all antigens. However, the increase in avidity to DT was not significant in the maternally-vaccinated group. In addition, post-booster avidity to PT was lower (mean 68.1% RAI) than in the non-maternally-vaccinated group (mean 78.7% RAI). Whether this difference is clinically significant is currently unknown, and individual RAI levels against PT in both groups all reach above the 40% “moderate” cut-off. However, this does mirror previous data from this group that show reduced PT titres in these infants post-booster.Citation11
It would be interesting for the avidity investigations presented in this current study to be extended to measure avidity following the initial vaccination course to generate more data on avidity dynamics between birth and 15 months. Studies from before maternal Tdap vaccination was introduced found that higher anti-pertussis maternal antibodies had no impact on infant's responses to acellular pertussis vaccines.Citation18,Citation19 However, evidence is accumulating that responses to the pediatric acellular vaccine are modulated by the elevated maternal antibody provided by maternal Tdap vaccination. A study in the UK showed that infants whose mothers had been vaccinated during pregnancy have lower post-vaccine anti-PT, FHA and FIM antibody titres than a historical cohort of infants from non-vaccinated pregnancies.Citation20 A controlled cohort study, from which the samples for this current study are derived, also demonstrated that infants’ born to Tdap-vaccinated mothers have a blunted antibody response against PT and DT following their first 3 doses of pertussis-containing vaccine.Citation10 Whether there is a difference in antibody avidities at these time-points is not known, and could provide useful data regarding the early functionality of antibody in infants born to maternally-vaccinated mothers.
One limitation of the study is that the method followed was optimised for assessing avidity of anti-FHA and –PT antibodies,Citation12 and the authors only retested the conditions for anti-PT before using the same conditions for all other antigens. As the original methods paperCitation12 stated that the “success of each dissociating agent in interrupting the antibody–antigen binding seems to be highly dependent on the kind of investigated antigen and its specific antibodies," it would have been prudent to test that the protocol was suitable for the additional antigens tested in this study. For example, the RAI of DT was generally lower than other antigens, but this could be because the conditions utilised were not optimal for this antigen. Almanzar et alCitation12 report that the assay is not suitable when antibody levels are < 1 IU/mL for IgG-anti-PT and < 5 IU/mL for IgG-anti-FHA. IU/ml levels against TT and DT in this cohort were both <1 IU/mL pre-booster and <5 IU/mL post-booster,Citation11 and the cut off for testing TT and DT avidity was not determined. Hendrikx et al. have reported using the same conditions for anti-Prn antibody avidity,Citation14 so it may be that the same concentration of NH4SCN is also suitable for this antigen, although Hendrikx et al. standardized antibody concentration before testing, which was not done in this current study. Given the simplicity and convenience of this assay, and the potential importance of measuring antibody avidity in vaccination studies, future efforts should be directed toward optimising this protocol for all antigens of interest in future antibody avidity studies. In addition, as pointed out by the current authors, this assay is likely to be most useful when assessing avidity “within a defined setting”, and care must be taken when comparing RAI scores across different sites.
The novel avidity data in this current study is encouraging, as it suggests that maternal Tdap vaccination has minor impact on the priming of immunological memory in infants both before and after their booster dose, although we should continue to monitor anti-PT avidity. No correlates of immunity have been defined for pertussis, but high antibody titres are associated with protection against disease.Citation21 The clinical significance of any blunting in antibody titres or avidity in infants born to vaccinated mothers remains unknown. Given the country-specific variability in timing of booster vaccination, it would be advantageous for these investigations to be repeated in other settings. It is clear that any additional information regarding antibody functionality, including data on antibody avidity, as presented in this current study, will be invaluable when assessing the impact of current and future maternal vaccination strategies.
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed.
Funding
TR is supported by the NIHR Imperial Biomedical Research Centre and BH and BK are supported by the MRC.
References
- Huygen K, Caboré RN, Maertens K, Van Damme P, Leuridan E. Humoral and cell mediated immune responses to a pertussis containing vaccine in pregnant and nonpregnant women. Vaccine 2015; 33:4117–23; PMID:26187257; https://doi.org/10.1016/j.vaccine.2015.06.108
- Dabrera G, Amirthalingam G, Andrews N, Campbell H, Ribeiro S, Kara E, Fry NK, Ramsay M. A case-control study to estimate the effectiveness of maternal pertussis vaccination in protecting newborn infants in England and wales, 2012–2013. Clin Infect Dis 2015; 60:333–7; https://doi.org/10.1093/cid/ciu821
- Amirthalingam G, Andrews N, Campbell H, Ribeiro S, Kara E, Donegan K, Fry NK, Miller E, Ramsay M. Effectiveness of maternal pertussis vaccination in England: an observational study. Lancet 2014; 384:1521–8; PMID:25037990; https://doi.org/10.1016/S0140-6736(14)60686-3
- Gall SA, Myers J, Pichichero M. Maternal immunization with tetanus-diphtheria-pertussis vaccine: effect on maternal and neonatal serum antibody levels. Am J Obstet Gynecol 2011; 204:334. e1-5; https://doi.org/10.1016/j.ajog.2010.11.024
- Vilajeliu A, Goncé A, López M, Costa J, Rocamora L, Ríos J, Teixidó I, Bayas JM; PERTU Working Group. Combined tetanus-diphtheria and pertussis vaccine during pregnancy: transfer of maternal pertussis antibodies to the newborn. Vaccine 2015; 33:1056–62; PMID:25573035; https://doi.org/10.1016/j.vaccine.2014.12.062
- Njie-Jobe J, Nyamweya S, Miles DJ, van der Sande M, Zaman S, Touray E, Hossin S, Adetifa J, Palmero M, Burl S, et al. Immunological impact of an additional early measles vaccine in Gambian children: responses to a boost at 3 years. Vaccine 2012; 30:2543–50; PMID:22314136; https://doi.org/10.1016/j.vaccine.2012.01.083
- Letson GW, Shapiro CN, Kuehn D, Gardea C, Welty TK, Krause DS, Lambert SB, Margolis HS. Effect of maternal antibody on immunogenicity of hepatitis A vaccine in infants. J Pediatr 2004; 144:327–32; https://doi.org/10.1016/j.jpeds.2003.11.030
- Halasa NB, Gerber MA, Chen Q, Wright PF, Edwards KM. Safety and Immunogenicity of Trivalent Inactivated Influenza Vaccine in Infants. J Infect Dis 2008; 197:1448–54; https://doi.org/10.1086/587643
- Caboré RN, Maertens K, Dobly A, Leuridan E, Van Damme P, Huygen K. Influence of maternal vaccination against diphtheria, tetanus, and pertussis on the avidity of infant antibody responses to a pertussis containing vaccine in Belgium. Virulence 2017; Advance online publication. https://doi.org/10.1080/21505594.2017.1296998
- Maertens K, Caboré RN, Huygen K, Hens N, Van Damme P, Leuridan E. Pertussis vaccination during pregnancy in Belgium: Results of a prospective controlled cohort study. Vaccine 2016; 34:142–50; PMID:26592142; https://doi.org/10.1016/j.vaccine.2015.10.100
- Maertens K, Caboré RN, Huygen K, Vermeiren S, Hens N, Van Damme P, Leuridan E. Pertussis vaccination during pregnancy in Belgium: Follow-up of infants until 1 month after the fourth infant pertussis vaccination at 15 months of age. Vaccine 2016; 34:3613–9; PMID:27142328; https://doi.org/10.1016/j.vaccine.2016.04.066
- Almanzar G, Ottensmeier B, Liese J, Prelog M. Assessment of IgG avidity against pertussis toxin and filamentous hemagglutinin via an adapted enzyme-linked immunosorbent assay (ELISA) using ammonium thiocyanate. J Immunol Methods 2013; 387:36–42; https://doi.org/10.1016/j.jim.2012.09.008
- Ibrahim NM, El-kady EM, Eissa SA, Wahby AF. Assessment of antibody level and avidity against Bordetella pertussis in a cohort of Egyptian individuals aged 1–18 years. J Adv Res 2016; 7:105–11; PMID:26843976; https://doi.org/10.1016/j.jare.2015.03.002
- Hendrikx LH, Berbers GA, Veenhoven RH, Sanders EA, Buisman AM. IgG responses after booster vaccination with different pertussis vaccines in Dutch children 4 years of age: Effect of vaccine antigen content. Vaccine 2009; 27:6530–6; PMID:19729085; https://doi.org/10.1016/j.vaccine.2009.08.052
- Abu Raya B, Bamberger E, Almog M, Peri R, Srugo I, Kessel A. Immunization of pregnant women against pertussis: The effect of timing on antibody avidity. Vaccine 2015; 33:1948–52; PMID:25744227; https://doi.org/10.1016/j.vaccine.2015.02.059
- Prelog M, Almanzar G, Rieber N, Ottensmeier B, Zlamy M, Liese J. Differences of IgG antibody avidity after an acellular pertussis (aP) booster in adolescents after a whole cell (wcP) or aP primary vaccination. Vaccine 2013; 31:387–93; PMID:23142306; https://doi.org/10.1016/j.vaccine.2012.10.105
- Barkoff AM, Gröndahl-Yli-Hannuksela K, Vuononvirta J, Mertsola J, Kallonen T, He Q. Differences in avidity of IgG antibodies to pertussis toxin after acellular pertussis booster vaccination and natural infection. Vaccine 2012; 30:6897–902; PMID:22981763; https://doi.org/10.1016/j.vaccine.2012.09.003
- Englund JA, Anderson EL, Reed GF, Decker MD, Edwards KM, Pichichero ME, Steinhoff MC, Rennels MB, Deforest A, Meade BD. The effect of maternal antibody on the serologic response and the incidence of adverse reactions after primary immunization with acellular and whole-cell pertussis vaccines combined with diphtheria and tetanus toxoids. Pediatrics 1995; 96:580–4; PMID:7659480
- Jones C, Pollock L, Barnett SM, Battersby A, Kampmann B. The relationship between concentration of specific antibody at birth and subsequent response to primary immunization. Vaccine 2014; 32:996–1002; PMID:24342250; https://doi.org/10.1016/j.vaccine.2013.11.104
- Ladhani SN, Andrews NJ, Southern J, Jones CE, Amirthalingam G, Waight PA, England A, Matheson M, Bai X, Findlow H, et al. Antibody responses after primary immunization in infants born to women receiving a pertussis-containing vaccine during pregnancy: single arm observational study with a historical comparator. Clin Infect Dis 2015; 61:1637–44; https://doi.org/10.1093/cid/civ695
- Cherry JD, Gornbein J, Heininger U, Stehr K. A search for serologic correlates of immunity to Bordetella pertussis cough illnesses. Vaccine 1998; 16:1901–6; PMID:9796041; https://doi.org/10.1016/S0264-410X(98)00226-6