Immunity from Tetanus as a representative element of previous immunization against Diphtheria-Tetanus-Pertussis in Migrant Children
The Pediatric Infectious Disease Journal
Isabel Garcia de la Fuente, Noémie Wagner, Claire-Anne Siegrist and Posfay-Barbe
Context: data on vaccination coverage in newly arrived refugee children are essential for making recovery recommendations. "Excess Immunization" is expensive and associated with the risks of hyperimmunization, while taking up-to-date vaccinations can be misleading. Methods: In retrospect we collected data from 92 migrant children referred to our hospital between January 2009 and May 2010.
Risultati: According to our guidelines, 68 children (73,9%) with no evidence of updated vaccinations received a booster dose of an age-appropriate vaccine containing tetanus. As a representative of immunity for diphtheria-tetanus-pertussis-poliomyelitis, antibodies against tetanus were measured by enzyme-linked immunosorbent assay 1 month later in 55 of 68 (80,8%) children aged 6 months to 16 years ( median, 7 years) from 23 countries. All but 2 children (3,6%) had achieved high antibody levels (> 1,0 IU / mL) and did not need further booster. Unnecessary additional tetanus immunizations were therefore avoided in 53 of 55 (96,4%) patients.
Conclusion: the evaluation of tetanus antibody responses in migrant children allows individual vaccination plans and avoids the risks of hyperimmunization.
Tetanus remains a major cause of vaccine-preventable morbidity and mortality despite the drastic reduction of the disease since the implementation of the World Health Organization's immunization programs and the introduction of universal vaccination. Globally, there are 1 million cases per year worldwide, with a mortality rate of up to 30-50%, which occurs mainly in developing countries.  In developed countries, immigrants from countries with economic problems, political refugees and adopted children represent a particularly vulnerable population due to unknown, incomplete or absent immunization. [2-7] Data on vaccination coverage against tetanus in immigrant children who have just arrived in Europe are absent. There is currently no universal guideline on how to recover immunization in migrant children without available or reliable vaccination records. Theoretically, there are several possibilities: serological tests on the first visit; serological test 1 month after a booster; or complete primary immunization (3 doses) with age-appropriate vaccines, regardless of previous vaccination. Unnecessary vaccination of children is associated with an increased risk of serious adverse reactions, such as hyperimmunization, which includes significant and painful local swelling, erythema or fever. Conversely, taking an updated vaccination history for granted can be misleading and can lead to vulnerability to vaccine-preventable diseases. This study reports the outcome of our strategy in which we measured the anti-tetanus antibody responses as a representative element for immunization against diphtheria-tetanus-pertussis-poliomyelitis in immigrant children after a single vaccination.
Methods and Materials
The demographic and clinical data of newly arrived immigrant children were analyzed retrospectively from hospital records between January 2009 and May 2010. The Geneva Pediatric Hospital, part of the university hospitals of Geneva, is the only center in our region which provides healthcare to all immigrant children arriving in our area, with particular attention to their health and the state of development and vaccination. When available, the personally reported vaccination status and the medical records available for immunization were examined.
Children with unavailable or incomplete diphtheria-tetanus-pertussis-poliomyelitis vaccination records received a single dose of an age-appropriate combination vaccine according to the Swiss recommendation to catch up with immunization of pertussis up to age 15 years old.  Children under 8 years of age received Infanrixhexa (DTPa-IPV-HBV / Hib) or Infanrix (DTPa-IPV / Hib, both from GlaxoSmithKline, Philadelphia, PA) if their hepatitis B immunization status was up to date. For those 8 years of age or older, combined vaccines were administered including tetanus toxoid, inactivated poliomyelitic viruses and a reduced dose of diphtheria toxoid without (Revoxis, Sanofi Pasteur MSD, Lyon, France) or with pertussis antigens ( Boostrix-polio; GlaxoSmithKline).
At the next visit, the adverse events of the vaccine were asked. Antibodies (IgG) against tetanus were measured 1 month after booster vaccination by enzyme-linked immunosorbent assays in the Vaccinology Laboratory of the University Hospitals of Geneva using standardized methods. Anti-tetanus IgG values of ≥0,1IU / mL and ≥ 1,0 IU / mL were considered to be correlated with short and long-term protection, respectively. Following the Swiss recommendations, 9 missing recovery immunizations were recommended for each patient, depending on age and antibody titers. This included 2 additional boosters for children with tetanus toxoid (TT) antibodies <0,5 IU / mL and a single additional booster for those with anti-TT antibodies between 0,5 and <1,0 IU / mL. 
Population of study
A total of 9 patients were evaluated. The children came from 23 countries, most of which came from Eastern Europe (39%) and sub-Saharan Africa (26%). Upon arrival in Switzerland, they were between 6 months and 16 years old (median, 7 years old). No children in this cohort were HIV positive.
Self-reported vaccination status and vaccination records
Only 4% (4 patients) had vaccination records. Based on the recall of the parents, 27% (25 patients, median age, 3,5 years) were considered updated with diphtheria-tetanus-pertussis (DTP) vaccination. A significant percentage of parents (of 18 children, 19,5%) reported previous vaccinations not made or incomplete in their home country. Almost half of the parents (of 45 children, 48%) remembered at least one injection of DTP in their children, but did not know if the children were updated on vaccinations.
Tetanus-containing vaccines were administered to 68 children, including 63 children with unknown or incomplete previous immunization. Five children updated with their DTP vaccinations received a routine age-based booster containing tetanus. At the 1-month follow-up visit, no serious local or systemic inflammatory adverse events were spontaneously reported, indicating good tolerance of this single booster.
Vaccine response to booster vaccination
Antibody responses after a single tetanus-containing vaccine were measured in 55 of 63 (87,3%) patients (aged less than 2 years: 2; 2-5 years: 12; 5-10 years: 19; 10- 16 years: 22) with unknown or incomplete prior immunization. All had achieved anti-TT titers> 0,1 IU / mL. We divided the patients into 3 groups: (1) patients with low antibody titers (<1,0 IU / mL) who required additional tetanus-containing boosters to ensure long-term protection; (2) patients with normal post-booster titers (1,0-10 IU / mL), who were recommended for subsequent booster according to the normal Swiss vaccination schedule,  and (3) patients with high antibody titers ( defined as> 10 IU / mL), for which the next recommended vaccination was postponed for 5-20 years depending on age and antibody titers. Only 2 patients (3,6%) (a 5-year-old from Turkey and a 9-year-old girl from Kosovo) had post-booster anti-TT titers <1,0 IU / mL, indicating incomplete immunity. Therefore, a single booster was sufficient for 53 patients (96,4%) to achieve elevated antibody levels (> 1,0 IU / mL) (Table 1). 63% of patients (n = 35) achieved anti-TT titers> 10 IU / mL, including 6 with very high antibody titers (≥30 IU / mL; Table 1), suggesting that they would not have required vaccine administration .
Relationship between the reported vaccination status and immunity
We found no relationship between the data reported through parental recall and the response to the virus. Eight patients had antibody titres> 10 IU / mL and 1 had antibody titres> 30 IU / mL, although they were reported as never or not fully vaccinated prior to their arrival.
Our study evaluated serological protection against tetanus in immigrant children. As in the studies on adult refugees, [10,11] a large percentage of immigrant children did not have vaccination records on arrival. While only about half of the patients' parents recalled that their children had received at least the tetanus vaccine dose, more than 96% of the children responded to a single vaccination with protective levels and therefore did not require additional update vaccinations. This represents a much higher rate of protection than predicted by the literature, in which only 35- 87% of adopted children or immigrant patients had protective levels of antibodies against tetanus. [4,12] This could be explained by a high percentage of children from Eastern Europe with, until recently, high vaccination coverage and the absence of children from China, which seems to be a particularly vulnerable population.  The effect of United Nations World Health Organization / Children's Fund campaigns in sub-Saharan Africa may also have played a role, but due to the heterogeneity of our population it was not possible to analyze each country separately. Furthermore, most of the children arrived in good clinical condition, without malnutrition or HIV infection, which may explain their good past and present immune capacity.
The serotest after a single vaccination identified sufficiently immunized children and avoided many unnecessary additional vaccinations. He identified the few children who most likely had never been vaccinated before or who had not generated enough memory B cells; their post-booster antibody levels remained <1,0 IU / mL. Although this has not been formally tested here, the serum response of a single (possibly "booster") vaccination is likely a better predictor of a previous tetanus vaccination / baseline immunity than baseline antibody measurements; post-immunization responses reflect the persistence and "recall" of specific memory B cells and may persist long after the antibody disappears. 
The results of our study should discourage starting complete vaccination programs without serological tests in immigrant children, because most children, even when they claim they have never been vaccinated, did not need a complete recovery. It could also expose them to the risk of hyperimmunization. Although mild adverse reactions to vaccination have not been systematically recorded in the patient records, no serious adverse reactions have been reported, even for our patients with very high antibody responses. This suggests that their basal tetanus titers were low at the time of recall, avoiding the generation of inflammatory immune complexes. Although this cannot be demonstrated, it is likely that the high or very high titres elicited after the first booster would have generated more serious adverse events if additional immunization had been empirically administered.
This study reports our results for tetanus immunity; however, immigrant children often have poor immune coverage for other vaccine-preventable diseases.  Recently, Paxton et al.  confirmed that almost all pediatric immigrants in their institution from East Africa had an unknown or incomplete vaccination status and only 15% of the children presented with serological immunity against tetanus, hepatitis B, diphtheria, rubella or measles. In addition, several authors also showed that even after resettlement, patients were not properly vaccinated and had missed many opportunities, such as medical visits, for the recovery of vaccinations. [5,14] Still today, immigrant children they remain a vulnerable group for health problems, despite the recommendations available. In our institute we design vaccination programs based on the patient's age, vaccination records (if available) and risk factors (Table 2). We usually administer a maximum of 3 vaccines simultaneously for convenience and inject live attenuated vaccines both simultaneously and 4 weeks apart, as recommended.  The recovery program started on the first visit and is completed as quickly as possible afterwards (2-6 months) to protect the children as quickly as possible and before their residence status is decided. All parents receive a copy of the vaccination records and the new primary pediatrician also receives a copy in case the children become resident. Our study was not designed as a cost analysis study. However, the costs of measuring antibody titers, which vary from country to country, were much lower than the costs of additional combined vaccines containing tetanus. In addition, we used an anesthetizing skin cream to significantly reduce the discomfort of phlebotomy, although this method has shown little effectiveness in reducing the discomfort of intradermal vaccination.
Our study has some limitations. First, we did not have enough patients to determine the predictive factors for vaccine responses based on the country of origin (and their vaccination schedules), age or gender. Larger studies would be needed to identify these subgroups and define vaccination strategies based on demographic data. Furthermore, since many of our patients came from Eastern Europe, it is possible that our conclusions do not apply to children from Asia or Latin America. Secondly, there is a small percentage of children who respond suboptimally to vaccination against tetanus as well. Therefore, it is possible that children with low antibody titers were "poor responders" rather than under vaccinated children. However, low responders benefit from additional boosters, making this difference more academic than clinically relevant. Third, antibody titers have not been evaluated before booster vaccination, precluding identification of the percentage of children in whom even the single booster could be avoided Consider our national guidelines to provide recovery immunization as soon as possible to migrant children who may not benefit from prolonged follow-up -up doctor, we should have done a clinical study design. Although this study is theoretically feasible, it was considered problematic in this vulnerable population that was unfamiliar with research studies, had communication problems, had interaction times limited and other factors. Finally, we opted eg r the determination of tetanus antibodies as a single representative element for immunization for DTP and childhood poliomyelitis, which can be oversimplified. It is possible that tetanus antibodies are not a good representative element of pertussis immunity since antibodies to pertussis seem to fade more quickly over time and require an earlier booster dose.  However, combined childhood vaccines containing inactivated tetanus, diphtheria and whooping cough and polio viruses are usually given at the time of DTP immunization, polio specific serology is neither readily available nor standardized and the risk of acquiring poliomyelitis is currently low in most countries.
All refugee children should be checked for vaccination status on arrival. We recommend measuring tetanus antibody titers after a single age-appropriate vaccination to evaluate tetanus immunity as a representative element of previous DTP and poliomyelitis vaccinations. This strategy allows individual customization of vaccination programs, avoids many unnecessary vaccinations and decreases the risk of hyperimmunization.
Translation by Claudio Andreini, CLiVa Tuscany