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Seroprotection rate in adults after 1-dose, 2-dose, and 3-dose series of a reduced-diphtheria-tetanus toxoid vaccine (Td) during a diphtheria outbreak in Thailand
Vaccine xxx (xxxx) xxx
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Short communication
Seroprotection rate in adults after 1-dose, 2-dose, and 3-dose series of a reduced-diphtheria-tetanus toxoid vaccine (Td) during a diphtheria outbreak in Thailand Piyarat Suntarattiwong a,b,⇑, Warunee Punpanich Vandepitte a,b, Pon Singhamatr c, Tawee Chotpitayasunondh a a
Queen Sirikit National Institute of Child Health, Bangkok, Thailand College of Medicine, Rangsit University, Bangkok, Thailand c Department of Pathology, Queen Sirikit National Institute of Child Health, Bangkok, Thailand b
a r t i c l e
i n f o
Article history: Received 22 September 2019 Received in revised form 6 January 2020 Accepted 11 January 2020 Available online xxxx Keywords: Diphtheria outbreak Diphtheria toxoid vaccine Diphtheria Adult vaccination Thailand immunization program
a b s t r a c t To evaluate seroprotection of different dosing strategies of reduced-diphtheria-tetanus-toxoid vaccine (Td) for adults during a diphtheria outbreak in Thailand, we enrolled 160 healthcare workers and 161 adults aged 20–60 years old and measured diphtheria antitoxin (DAT) level before administration of a Td vaccine. We scheduled a second Td at 4–8 weeks and a third Td at 6–12 months interval. DAT was measured 4 weeks after each dose. DAT levels of 0.1 and 1 IU/mL were considered as seroprotective and long-term seroprotective. Persons achieving long-term seroprotection were not given a further dose. The baseline seroprotection rate was 32.6%, which increased to 87.1% (95% confidence interval, 83.4– 90.8%) after one dose. The seroprotection rate increased slightly with additional doses. The immune response was lowest among persons 30–49 years of age. We suggest 1-dose Td for adults during a diphtheria outbreak, and a 2-dose series being considered for those born before 1980. Ó 2020 Elsevier Ltd. All rights reserved.
1. Introduction The global incidence of diphtheria decreased substantially after the introduction of diphtheria-tetanus-pertussis (DTP) vaccine. However, since 2010, the waning of immunity over time and scattered pockets of unvaccinated populations have resulted in diphtheria outbreaks in many parts of the world with four outbreaks being reported in Southeast Asia including Lao PDR, Indonesia, Vietnam, and Thailand [1–4]. In an outbreak situation, healthcare workers are at risk due to their occupational exposure, thereby requiring specific attention for immunization against diphtheria [5]. During a 2012–2013 diphtheria outbreak in Thailand, the Thai Ministry of Public Health recommended a reduced-diphtheriatetanus toxoid vaccine (Td) to boost protection against diphtheria. Although one booster dose is adequate to promote immunity, three doses of the diphtheria-toxoid-containing vaccine are recommended for individuals who have not been previously vaccinated [5]. Thailand achieved control of diphtheria after the launch of the Expanded Program on Immunization (EPI) in the late 1970s. How-
ever, before 1989, the diphtheria toxoid vaccine coverage was less than 80%. This means that some adults born in the 1970s and 1980s are naive to diphtheria vaccination, and a decline in disease prevalence has also resulted in less naturally-acquired immunity [6]. From June 2012 to January 2013, a resurgence of 43 cases of adult diphtheria was reported in several provinces of Thailand [4], and as a result, the Thai Ministry of Public Health advised of the necessity for diphtheria toxoid-containing vaccines for healthcare workers and people residing in outbreak areas. For most of the adult population, including healthcare workers, vaccination statuses were insufficiently documented. Therefore, it was uncertain how many doses of Td would be required to achieve seroprotection. We studied baseline seroprotection rates, immunogenicity, and reactogenicity after one to three doses of Td in Thai healthcare workers and a convenience sample of the general adult population. This was undertaken in order to add to the evidence-base to support diphtheria immunization recommendations during an outbreak.
2. Material and methods ⇑ Corresponding author at: Queen Sirikit National Institute of Child Health, 420/8 Rajavithi Road, Bangkok 10400, Thailand. E-mail address: [email protected] (P. Suntarattiwong).
At Queen Sirikit National Institute of Child Health, a government tertiary care children’s hospital in Bangkok, Td vaccine was
https://doi.org/10.1016/j.vaccine.2020.01.040 0264-410X/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: P. Suntarattiwong, W. P. Vandepitte, P. Singhamatr et al., Seroprotection rate in adults after 1-dose, 2-dose, and 3-dose series of a reduced-diphtheria-tetanus toxoid vaccine (Td) during a diphtheria outbreak in Thailand, Vaccine, https://doi.org/10.1016/j.vaccine.2020.01.040
2
P. Suntarattiwong et al. / Vaccine xxx (xxxx) xxx
offered to healthcare workers and the caregivers of children beginning in January 2013. The vaccine was manufactured by Serum Institute of India LTD, containing 2 IU of diphtheria toxoid and 20 IU of tetanus toxoid per 0.5 mL-dose, Lot No. 02311008A. We recruited a convenience sample of healthcare workers and caregivers of hospitalized children who were 20–60 years of age, from January 1 to March 31, 2013. Persons who had received a diphtheria toxoid-containing vaccine within the previous 5 years or had comorbidity requiring treatment with immunosuppressive drugs were excluded. After obtaining informed consent, we collected 3–5 mL of blood to test for baseline diphtheria toxoid antibody before administering the Td vaccine. A 3-dose series was provided as per the recommended schedule for diphtheria toxoid-containing vaccines in unvaccinated adults. A second dose was given 4–8 weeks after the first dose, and a third dose 6– 12 months after the second [7]. We measured anti-diphtheria toxin immunoglobulin G titer (DAT) using enzyme-linked immunosorbent assay kits (ERIEI2040-9601G, EUROIMMUN AG, Germany) at baseline and 4 weeks after each vaccine dose. A DAT level of 0.01 IU/mL to less than 0.1 IU/mL was considered partially protective, 0.1 IU/mL or greater was considered protective (seroprotection), and a DAT level of 1.0 IU/mL or greater was considered long-term protective [7]. Persons whose antibody levels reached that indicative of longterm protection for diphtheria were excluded from receiving a further Td dose. After administration of the vaccine, participants were observed for 30 min, after which they were asked to complete a symptom diary card for solicited adverse events for a further 7 days and were advised to record any adverse event for up to 30 days. The sample size calculation was based on the assumption that 75% of the population required one dose of Td to achieve seroprotection [6]. We planned to enroll equal numbers of healthcare workers and non-healthcare workers with equal numbers of each 10-year age range to be representative. Using a margin of error of 0.05 and a confidence level of 95%, accounting for the agegroup stratification, the desired sample size was 296 (74 for each age-group stratum). Allowing for an approximately 10% drop-out rate, we enrolled 320 subjects (80 for each age-group). Descriptive statistics were used to report the proportion of the population who attained seroprotection with a 95% confidence interval at baseline and whether a 1-dose, 2-dose, or 3-dose series of Td was recommended. We used Chi-square tests to determine an association between age group, healthcare worker status, and the recall of receiving vaccines in the EPI with seroprotection at baseline and after each dose of Td. For predictors with a significant association in univariate analysis, we applied logistic regression analysis to identify independent predictors of seroprotection. Statistical analysis was performed using SPSS version 16.0 (SPSS Inc., Chicago IL, USA). A p-value of less than 0.05 was considered statistically significant. The study protocol was approved by the Queen Sirikit National Institute of Child Health Research Ethics Committee (Document EC.046/2556), and all of the participants provided written informed consent.
The enrolled healthcare workers were comprised of 61 nurse assistants, 52 nurses, 29 pharmacists, 8 lab technicians, 6 housekeepers, 3 hospital porters, and 1 doctor. The majority (72.5%) had been working in the hospital for more than 5 years. Of the 321 participants, 16 had a baseline DAT level 1.0 IU/mL (long-term protective level), and 2 healthcare workers declined to continue. The DAT levels at 4 weeks after the first dose were not available before the scheduled second dose of Td. Therefore, 303 participants received a 2-dose series of the Td vaccine. After two doses, 161 of the remaining 303 participants had a DAT level 1.0 IU/mL and as such, 142 participants received a 3-dose series (Fig. 1). Excluding the two who dropped out, we analyzed data from 319 participants to identify the proportion achieving seroprotection at baseline, and whether a 1-dose, 2-dose, or 3-dose series of Td was recommended. One hundred four participants (32.6%, 95% CI: 27.4–37.8%) had a baseline DAT level considered to provide protection against diphtheria (0.1 IU/mL). The proportion of participants with baseline seroprotection varied significantly among age groups and was highest in persons aged 20–29 years (46.3%) and lowest in those aged 30–39 years (22.8%). In multivariable analyses, persons aged 20–29 years were 2.9 times more likely to have seroprotective diphtheria titers than those aged 30–39 years (95% CI: 1.4–5.8). Baseline seroprotection did not differ significantly between healthcare workers and non-healthcare workers, or between those who could recall previously receiving DTP vaccines and those who could not (Table 1). Of the 319 participants, 80 (25.1%) had a baseline DAT level of less than 0.01 IU/mL, a partially protective level. After one dose, 278 participants (87.1%, 95% CI: 83.4–90.8%) attained a DAT level that was considered protective against diphtheria (0.1 IU/mL). The proportion who achieved seroprotection after 1 dose varied significantly among age groups and was highest in persons aged 20–29 years (96.3%) and lowest in those aged 40– 49 years (82.3%). In the multivariable analyses, persons aged 20– 29 years were 5.2 times more likely to achieve seroprotection against diphtheria after one dose compared to those aged 30– 39 years (95% CI: 1.4–19.1). Healthcare workers were 2.1 times more likely to achieve seroprotection after one dose when compared to non-healthcare workers (95% CI: 1.0–4.2). However, the seroprotection rate did not significantly differ between those who could and could not recall whether they had been previously vaccinated in the Thai EPI program (Table 1). After a 2-dose series, the proportion of participants achieving seroprotection against diphtheria increased slightly to 90.9% (95% CI: 87.7–94.1%) and did not vary significantly by age groups, working status, or recall of previous EPI immunization. After a 3-dose series, 95.9% (95% CI: 93.7–98.1%) achieved seroprotection against diphtheria (Table 1). Of the 319 participants, 13 (4.1%) had a DAT level of less than 0.01 IU/mL after one dose. Two participants (0.6%) and one (0.3%)
321 received 1 dose 4-8 weeks
3. Results
16 Baseline DAT ≥ 1 IU/mL 2 Drop-out
303 received 2 doses A total of 160 healthcare workers and 161 non-healthcare workers were enrolled, of whom, 13 (8.1%) and 57 (35.4%) respectively were male. None of them had a history of recent travel to provinces with diphtheria outbreaks and only one reported a previous diphtheria disease exposure. One hundred eighty-eight (58.6%) recalled that they had already received vaccines in the EPI program, but none could provide a vaccination record.
6-12 months
161 DAT ≥ 1 IU/mL
142 received 3 doses Fig. 1. The timing and numbers of participants receiving one, two, and three doses of reduced-diphtheria-tetanus toxoid vaccine (Td).
Please cite this article as: P. Suntarattiwong, W. P. Vandepitte, P. Singhamatr et al., Seroprotection rate in adults after 1-dose, 2-dose, and 3-dose series of a reduced-diphtheria-tetanus toxoid vaccine (Td) during a diphtheria outbreak in Thailand, Vaccine, https://doi.org/10.1016/j.vaccine.2020.01.040
3
.047– 306 95.9 (93.7–98.1) 290 90.9 (87.7–94.1)
90.9 (86.7–95.0) 91.0 (86.0–95.9)
.357 92.4 (88.2–96.6) 89.4 (84.6–94.2)
Adverse event
.971
97.9 (95.8–100) 93.2 (88.9–97.6)
.751 95.6 (92.3–98.8) 96.3 (93.3–99.2)
.108 .123
100 92.4 (86.4–98.4) 96.2 (91.9–100) 95.1 (90.2–99.9) (92.0–100) (78.3–93.9) (81.4–95.8) (86.8–98.4) 96.3 86.1 88.6 92.6
2-dose series (95% CI)§
Table 2 Solicited adverse events after the first, second, and third dose.
–
–
§
104 32.6 (27.4–37.8) Number with seroprotection Percentage
Proportions shown are row percentages. * p-value from univariate analysis. Multivariable analysis gave an odds ratio of 3.9 (95% CI, 0.9–16.4).
278 87.1 (83.4–90.8)
88.7 (84.1–93.3) 85.0 (78.8–91.1) – .291 Recall of previous EPI immunization (n) Yes (186) 35.0 (28.0–41.9) Unsure or never (133) 29.3 (21.5–37.2)
1st dose (n = 319)
2nd dose (n = 303)
3rd doses (n = 142)
Local reaction Any pain Grade 3 pain*
197 (61.8) 1 (0.3)
118 (38.9) 2 (0.7)
62 (43.7) 1 (0.7)
Any redness 5 cm redness
24 (7.5) 7 (2.2)
37 (12.2) 5 (1.7)
14 (9.9) 0 (0)
Any swelling 5 cm swelling
39 (12.2) 6 (1.9)
34 (11.2) 5 (1.7)
14 (9.9) 1 (0.7)
Systemic reaction Any fever 39.5 °C
8 (2.5) 0 (0.0)
6 (2.0) 0 (0.0)
4 (2.8) 0 (0.0)
Any headache Grade 3 headache*
46 (14.4) 0 (0.0)
28 (9.2) 0 (0.0)
11 (7.7) 0 (0)
Any myalgia Grade 3 myalgia*
99 (31.0) 0 (0.0)
71 (23.4) 0 (0.0)
35 (24.6) 1 (0.7)
Grade 3 = Symptoms preventing normal daily activity.
had a level of less than 0.01 IU/mL after a 2-doses and a 3-doses series respectively. The most common adverse event was pain at the injection site, which was reported in 61.8%, 38.9%, and 43.7% of participants after the first, second, and third doses respectively. Severe solicited adverse events that were considered grade 3 included symptoms that prevented normal daily activities, a temperature higher than 39.5 °C, and local swelling or erythema of more than 5 cm. After the first, second, and third doses, 0.3%, 0.7%, and 0.7% of participants reported grade 3 pain at the injection site and 2.2%, 1.7%, and 0.7% of participants reported grade 3 local swelling or erythema. None reported temperature higher than 39.5 °C or grade 3 headaches. However, one participant reported grade 3 myalgia after the third dose (Table 2). An episode of a serious adverse event related to the vaccine was reported by a healthcare worker, who developed marked pain and swelling at the injection site after the first Td dose that required hospitalization. The participant recovered completely after seven days and was suspected to have experienced a reaction from her prior immunization with two doses of tetanus toxoid approximately five years before the current Td vaccine. Due to an inadequate level of seroprotection against diphtheria, the participant decided to continue and received the second and third dose of Td with lesser pain and swelling when compared to the first dose.
.324
2.1 (1.0–4.2) Ref. .035 91.1 (86.7–95.6) 83.2 (77.4–89.1) 37.3 (29.7–45.0) 28.0 (20.9–35.0)
.014
Working status (n) Healthcare worker (158) Non–healthcare worker (161)
(35.1–57.4) (13.3–32.2) (18.9–39.4) (21.7–42.4) 46.3 22.8 29.1 32.1 Age group (n) 20–29 year (80) 30–39 year (79) 40–49 year (79) 50–59 year (81)
.074
–
.036
5.2 (1.4–19.1) Ref. 0.9 (0.4–2.2) 1.2 (0.5–3.3) 96.3 83.5 82.3 86.4 2.9 (1.4–5.8) Ref. 1.5 (0.7–3.2) 1.7 (0.8–3.9)
(92.0–100) (75.2–92.0) (73.7–90.9) (78.8–94.0)
1-dose (95% CI)§ Baseline (95% CI)§
p-value*
Multivariable analysis: Odds Ratio (95% CI)
p-value*
Multivariable analysis: Odds Ratio (95% CI)
*
Characteristics (N=319)
Table 1 The proportion of individuals with seroprotection (DAT 0.1 IU/mL) at baseline and after a 1-dose, 2-dose, and 3-dose series of Td and predictors of seroprotection.
p-value*
3-dose series (95% CI)
p-value*
P. Suntarattiwong et al. / Vaccine xxx (xxxx) xxx
4. Discussion This study demonstrated that approximately two-thirds of the Thai adult population including most healthcare workers in Bangkok were not protected against diphtheria during Thailand’s 2012– 2013 diphtheria outbreak. Furthermore, approximately one-fourth had diphtheria antitoxin levels below a minimal protective level, which made them highly susceptible to the disease [7]. Overall the baseline seroprotection rates observed here are similar to findings from a large diphtheria immunity study in Turkey, where approximately 50% of adults from 20 to 60 years old had protective immunity against diphtheria [8]. However, our baseline seroprotection rates were much lower when compared to findings from a seroprevalence study in Thailand during the same period [4]. We postulate that while our study population resided in Bangkok, their population was from remote areas of the country and as such, there might be some diversities including possible diphtheria exposures among partially immune population and repeated subclinical infection to acquire immunity, or the variation of
Please cite this article as: P. Suntarattiwong, W. P. Vandepitte, P. Singhamatr et al., Seroprotection rate in adults after 1-dose, 2-dose, and 3-dose series of a reduced-diphtheria-tetanus toxoid vaccine (Td) during a diphtheria outbreak in Thailand, Vaccine, https://doi.org/10.1016/j.vaccine.2020.01.040
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P. Suntarattiwong et al. / Vaccine xxx (xxxx) xxx
vaccination coverage both primary and booster vaccines in different areas of the country. We observed the 30–49 year age group to have the lowest rates of seroprotection, whereas the 20–29 year age group had the highest at baseline and at after one dose of Td. These are similar to findings from both of the studies previously mentioned [4,8]. A diphtheria disease and vaccination coverage survey report showed that the 30–49 year age group had probably received less than three doses of DTP during their childhood at the beginning of EPI program in Thailand [6]. This underlined the importance of primary diphtheria immunization coverage in infants, as well as a programmatic booster vaccination after childhood. Regarding the maintenance of tetanus and diphtheria immunity in Thailand, decennial boosting with Td has been recommended. Nevertheless, less than 60% of Thai adults, including the healthcare workers in this study can recall receiving a diphtheria vaccine, suggesting the need to strengthen Thailand’s adult vaccination program. Immune response was induced to a seroprotective level with one dose of Td in 87% (95% CI: 83–91%) of our study population. Evidence from the prevaccine era suggested the estimated herd immunity threshold to be between 80% and 85% vaccine coverage [7]. This implies that vaccinating 80–85% of the population could prevent people in the community from contracting diphtheria. Moreover, any possible breakthrough disease would likely be mild among immunized individuals. Therefore, from a public health perspective, a single dose of Td may be a sufficient recommendation for the general population of adults and healthcare workers during a diphtheria outbreak, which would be in agreement with the recommendations from a seroprevalence study conducted in Thailand [4] and practices during a more recent outbreak in South Africa [9]. Although no level of antitoxin confers absolute protection against diphtheria and there were reported cases of fatal diphtheria in individuals with a high level of antitoxin, it has been concluded that an antitoxin level of 0.01 IU/mL is the lowest level that provides some degree of protection in most circumstances [7]. After one dose of Td, 4% of the study population still had serum antitoxin levels below 0.01 IU/mL. This proportion was reduced to 0.6% and 0.3% after two and three doses respectively. A 2-dose series of Td could be considered for individual protection of persons at risk of exposure to diphtheria, particularly those presumedly naive to the diphtheria toxoid-containing vaccine, e.g., healthcare workers born before 1980 when DTP coverage in Thailand was less than 80% [6]. A self-reported history of previous immunization in the EPI program without documentation did not show a significant difference in seroprotection after one or two doses of Td and is not useful for vaccination planning. Regardless of vaccination status, standard post-exposure management, including antimicrobial prophylaxis, must be administered for persons in close contact with diphtheria [10]. This study has some limitations. Firstly, the data arose from convenience samples at a tertiary care hospital, therefore, might not be fully representative of the underlying population. We did not include adults older than 60 years of age and cannot be generalized to that age group. Also, the majority of our study population were female gender. However, the baseline seroprotection rate as well as after each dose were similar between male and female in our study. The adverse events following each dose also must be interpreted with caution because approximately 4% and 55% of the participants with very high antitoxin levels were excluded from receiving their second and third doses respectively. Nevertheless, adverse events after the first and second doses were very similar, despite half of the participants already having antitoxin levels above 1 IU/mL before receiving their second doses. We concluded that one dose of Td should be recommended for adults during a diphtheria outbreak, with the option for a 2-dose series for healthcare workers born before 1980. A booster vaccination program for
adults, particularly for healthcare workers against emerging vaccine-preventable diseases such as diphtheria and pertussis [11,12] must be implemented. CRediT authorship contribution statement Piyarat Suntarattiwong: Conceptualization, Methodology, Project administration, Data curation, Writing - original draft, Writing - review & editing. Warunee Punpanich Vandepitte: Conceptualization, Methodology. Pon Singhamatr: Investigation. Tawee Chotpitayasunondh: Conceptualization, Methodology, Funding acquisition, Resources. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgement We would like to thank Dr. Siraporn Sawasdivorn, the former Director of Queen Sirikit National Institute of Child Health and Ms. Thasanan Aumprasert, Hospital Infection Control Head Nurse for their support in facilitating this study. Also, we would like to thank Dr. Joshua Mott, CDC Influenza Regional Program in Bangkok, Thailand for his English language review of the manuscript. Funding This work was supported by the Department of Medical Services Research Fund, Thai Ministry of Public Health. References [1] Acosta AM, Tiwari TSP. Diphtheria. In: Ryan ET, Hill DR, Solomon T, Aronson NE, Endy TP, editors. Hunter’s Tropical Medicine and Emerging Infectious Diseases (Tenth Edition). London: Elsevier; 2020: p. 439–45. [2] Hughes GJ, Mikhail AF, Husada D, et al. Seroprevalence and determinants of immunity to diphtheria for children living in two districts of contrasting incidence during an outbreak in East Java, Indonesia. Pediatr Infect Dis J 2015;34:1152–6. https://doi.org/10.1097/inf.0000000000000846. [3] Sein C, Tiwari T, Macneil A, et al. Diphtheria outbreak in Lao People’s Democratic Republic, 2012–2013. Vaccine 2016;34:4321–6. https://doi.org/ 10.1016/j.vaccine.2016.06.074. [4] Wanlapakorn N, Yoocharoen P, Tharmaphornpilas P, Theamboonlers A, Poovorawan Y. Diphtheria outbreak in Thailand, 2012; seroprevalence of diphtheria antibodies among Thai adults and its implications for immunization programs. Southeast Asian J Trop Med Public Health 2014;45:1132–41. [5] World Health Organization. Diphtheria vaccine: WHO position paper, August 2017 - Recommendations. Vaccine 2018;36:199–201. https://doi.org/10.1016/ j.vaccine.2017.08.024. [6] Tharmaphornpilas P, Yoocharoan P, Prempree P, Youngpairoj S, Sriprasert P, Vitek CR. Diphtheria in Thailand in the 1990s. J Infect Dis 2001;184:1035–40. https://doi.org/10.1086/323453. [7] Tiwari TSP, Wharton M. Diphtheria toxoid. In: Plotkin SA, Orenstein WA, Offit PA, Edwards KM, editors. Plotkin’s Vaccines (Seventh Edition). Philadelphia: Elsevier; 2018: 261–75.e7. https://doi.org/10.1016/B978-0-323-35761-6. 00019-5. [8] Kurugol Z, Midyat L, Turkoglu E, Isler A. Immunity against diphtheria among children and adults in Izmir, Turkey. Vaccine 2011;29:4341–4. https://doi.org/ 10.1016/j.vaccine.2011.04.016. [9] Mahomed S, Archary M, Mutevedzi P, et al. An isolated outbreak of diphtheria in South Africa, 2015. Epidemiol Infect 2017;145:2100–8. https://doi.org/ 10.1017/s0950268817000851. [10] American Academy of Pediatrics. Diphtheria. In: Kimberlin DW Brady MT, Jackson MA, Long SS, editors. Red Book: 2018 Report of the Committee on Infectious Diseases. 31 ed. Itasca, IL: American Academy of Pediatrics; 2018: 319–23. [11] Sangal L, Joshi S, Anandan S, et al. Resurgence of diphtheria in North Kerala, India, 2016: Laboratory Supported Case-Based Surveillance Outcomes. Front Public Health 2017;5:218. https://doi.org/10.3389/fpubh.2017.00218. [12] Suntarattiwong P, Kanjanabura K, Laopipattana T, Kerdsin A, Paveenkittiporn W, Chotpitayasunondh T. Pertussis surveillance in a children hospital in Bangkok, Thailand. Int J Infect Diseases 2019;81:43–5. https://doi.org/ 10.1016/j.ijid.2019.01.031.
Please cite this article as: P. Suntarattiwong, W. P. Vandepitte, P. Singhamatr et al., Seroprotection rate in adults after 1-dose, 2-dose, and 3-dose series of a reduced-diphtheria-tetanus toxoid vaccine (Td) during a diphtheria outbreak in Thailand, Vaccine, https://doi.org/10.1016/j.vaccine.2020.01.040
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Short communication
Seroprotection rate in adults after 1-dose, 2-dose, and 3-dose series of a reduced-diphtheria-tetanus toxoid vaccine (Td) during a diphtheria outbreak in Thailand Piyarat Suntarattiwong a,b,⇑, Warunee Punpanich Vandepitte a,b, Pon Singhamatr c, Tawee Chotpitayasunondh a a
Queen Sirikit National Institute of Child Health, Bangkok, Thailand College of Medicine, Rangsit University, Bangkok, Thailand c Department of Pathology, Queen Sirikit National Institute of Child Health, Bangkok, Thailand b
a r t i c l e
i n f o
Article history: Received 22 September 2019 Received in revised form 6 January 2020 Accepted 11 January 2020 Available online xxxx Keywords: Diphtheria outbreak Diphtheria toxoid vaccine Diphtheria Adult vaccination Thailand immunization program
a b s t r a c t To evaluate seroprotection of different dosing strategies of reduced-diphtheria-tetanus-toxoid vaccine (Td) for adults during a diphtheria outbreak in Thailand, we enrolled 160 healthcare workers and 161 adults aged 20–60 years old and measured diphtheria antitoxin (DAT) level before administration of a Td vaccine. We scheduled a second Td at 4–8 weeks and a third Td at 6–12 months interval. DAT was measured 4 weeks after each dose. DAT levels of 0.1 and 1 IU/mL were considered as seroprotective and long-term seroprotective. Persons achieving long-term seroprotection were not given a further dose. The baseline seroprotection rate was 32.6%, which increased to 87.1% (95% confidence interval, 83.4– 90.8%) after one dose. The seroprotection rate increased slightly with additional doses. The immune response was lowest among persons 30–49 years of age. We suggest 1-dose Td for adults during a diphtheria outbreak, and a 2-dose series being considered for those born before 1980. Ó 2020 Elsevier Ltd. All rights reserved.
1. Introduction The global incidence of diphtheria decreased substantially after the introduction of diphtheria-tetanus-pertussis (DTP) vaccine. However, since 2010, the waning of immunity over time and scattered pockets of unvaccinated populations have resulted in diphtheria outbreaks in many parts of the world with four outbreaks being reported in Southeast Asia including Lao PDR, Indonesia, Vietnam, and Thailand [1–4]. In an outbreak situation, healthcare workers are at risk due to their occupational exposure, thereby requiring specific attention for immunization against diphtheria [5]. During a 2012–2013 diphtheria outbreak in Thailand, the Thai Ministry of Public Health recommended a reduced-diphtheriatetanus toxoid vaccine (Td) to boost protection against diphtheria. Although one booster dose is adequate to promote immunity, three doses of the diphtheria-toxoid-containing vaccine are recommended for individuals who have not been previously vaccinated [5]. Thailand achieved control of diphtheria after the launch of the Expanded Program on Immunization (EPI) in the late 1970s. How-
ever, before 1989, the diphtheria toxoid vaccine coverage was less than 80%. This means that some adults born in the 1970s and 1980s are naive to diphtheria vaccination, and a decline in disease prevalence has also resulted in less naturally-acquired immunity [6]. From June 2012 to January 2013, a resurgence of 43 cases of adult diphtheria was reported in several provinces of Thailand [4], and as a result, the Thai Ministry of Public Health advised of the necessity for diphtheria toxoid-containing vaccines for healthcare workers and people residing in outbreak areas. For most of the adult population, including healthcare workers, vaccination statuses were insufficiently documented. Therefore, it was uncertain how many doses of Td would be required to achieve seroprotection. We studied baseline seroprotection rates, immunogenicity, and reactogenicity after one to three doses of Td in Thai healthcare workers and a convenience sample of the general adult population. This was undertaken in order to add to the evidence-base to support diphtheria immunization recommendations during an outbreak.
2. Material and methods ⇑ Corresponding author at: Queen Sirikit National Institute of Child Health, 420/8 Rajavithi Road, Bangkok 10400, Thailand. E-mail address: [email protected] (P. Suntarattiwong).
At Queen Sirikit National Institute of Child Health, a government tertiary care children’s hospital in Bangkok, Td vaccine was
https://doi.org/10.1016/j.vaccine.2020.01.040 0264-410X/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: P. Suntarattiwong, W. P. Vandepitte, P. Singhamatr et al., Seroprotection rate in adults after 1-dose, 2-dose, and 3-dose series of a reduced-diphtheria-tetanus toxoid vaccine (Td) during a diphtheria outbreak in Thailand, Vaccine, https://doi.org/10.1016/j.vaccine.2020.01.040
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P. Suntarattiwong et al. / Vaccine xxx (xxxx) xxx
offered to healthcare workers and the caregivers of children beginning in January 2013. The vaccine was manufactured by Serum Institute of India LTD, containing 2 IU of diphtheria toxoid and 20 IU of tetanus toxoid per 0.5 mL-dose, Lot No. 02311008A. We recruited a convenience sample of healthcare workers and caregivers of hospitalized children who were 20–60 years of age, from January 1 to March 31, 2013. Persons who had received a diphtheria toxoid-containing vaccine within the previous 5 years or had comorbidity requiring treatment with immunosuppressive drugs were excluded. After obtaining informed consent, we collected 3–5 mL of blood to test for baseline diphtheria toxoid antibody before administering the Td vaccine. A 3-dose series was provided as per the recommended schedule for diphtheria toxoid-containing vaccines in unvaccinated adults. A second dose was given 4–8 weeks after the first dose, and a third dose 6– 12 months after the second [7]. We measured anti-diphtheria toxin immunoglobulin G titer (DAT) using enzyme-linked immunosorbent assay kits (ERIEI2040-9601G, EUROIMMUN AG, Germany) at baseline and 4 weeks after each vaccine dose. A DAT level of 0.01 IU/mL to less than 0.1 IU/mL was considered partially protective, 0.1 IU/mL or greater was considered protective (seroprotection), and a DAT level of 1.0 IU/mL or greater was considered long-term protective [7]. Persons whose antibody levels reached that indicative of longterm protection for diphtheria were excluded from receiving a further Td dose. After administration of the vaccine, participants were observed for 30 min, after which they were asked to complete a symptom diary card for solicited adverse events for a further 7 days and were advised to record any adverse event for up to 30 days. The sample size calculation was based on the assumption that 75% of the population required one dose of Td to achieve seroprotection [6]. We planned to enroll equal numbers of healthcare workers and non-healthcare workers with equal numbers of each 10-year age range to be representative. Using a margin of error of 0.05 and a confidence level of 95%, accounting for the agegroup stratification, the desired sample size was 296 (74 for each age-group stratum). Allowing for an approximately 10% drop-out rate, we enrolled 320 subjects (80 for each age-group). Descriptive statistics were used to report the proportion of the population who attained seroprotection with a 95% confidence interval at baseline and whether a 1-dose, 2-dose, or 3-dose series of Td was recommended. We used Chi-square tests to determine an association between age group, healthcare worker status, and the recall of receiving vaccines in the EPI with seroprotection at baseline and after each dose of Td. For predictors with a significant association in univariate analysis, we applied logistic regression analysis to identify independent predictors of seroprotection. Statistical analysis was performed using SPSS version 16.0 (SPSS Inc., Chicago IL, USA). A p-value of less than 0.05 was considered statistically significant. The study protocol was approved by the Queen Sirikit National Institute of Child Health Research Ethics Committee (Document EC.046/2556), and all of the participants provided written informed consent.
The enrolled healthcare workers were comprised of 61 nurse assistants, 52 nurses, 29 pharmacists, 8 lab technicians, 6 housekeepers, 3 hospital porters, and 1 doctor. The majority (72.5%) had been working in the hospital for more than 5 years. Of the 321 participants, 16 had a baseline DAT level 1.0 IU/mL (long-term protective level), and 2 healthcare workers declined to continue. The DAT levels at 4 weeks after the first dose were not available before the scheduled second dose of Td. Therefore, 303 participants received a 2-dose series of the Td vaccine. After two doses, 161 of the remaining 303 participants had a DAT level 1.0 IU/mL and as such, 142 participants received a 3-dose series (Fig. 1). Excluding the two who dropped out, we analyzed data from 319 participants to identify the proportion achieving seroprotection at baseline, and whether a 1-dose, 2-dose, or 3-dose series of Td was recommended. One hundred four participants (32.6%, 95% CI: 27.4–37.8%) had a baseline DAT level considered to provide protection against diphtheria (0.1 IU/mL). The proportion of participants with baseline seroprotection varied significantly among age groups and was highest in persons aged 20–29 years (46.3%) and lowest in those aged 30–39 years (22.8%). In multivariable analyses, persons aged 20–29 years were 2.9 times more likely to have seroprotective diphtheria titers than those aged 30–39 years (95% CI: 1.4–5.8). Baseline seroprotection did not differ significantly between healthcare workers and non-healthcare workers, or between those who could recall previously receiving DTP vaccines and those who could not (Table 1). Of the 319 participants, 80 (25.1%) had a baseline DAT level of less than 0.01 IU/mL, a partially protective level. After one dose, 278 participants (87.1%, 95% CI: 83.4–90.8%) attained a DAT level that was considered protective against diphtheria (0.1 IU/mL). The proportion who achieved seroprotection after 1 dose varied significantly among age groups and was highest in persons aged 20–29 years (96.3%) and lowest in those aged 40– 49 years (82.3%). In the multivariable analyses, persons aged 20– 29 years were 5.2 times more likely to achieve seroprotection against diphtheria after one dose compared to those aged 30– 39 years (95% CI: 1.4–19.1). Healthcare workers were 2.1 times more likely to achieve seroprotection after one dose when compared to non-healthcare workers (95% CI: 1.0–4.2). However, the seroprotection rate did not significantly differ between those who could and could not recall whether they had been previously vaccinated in the Thai EPI program (Table 1). After a 2-dose series, the proportion of participants achieving seroprotection against diphtheria increased slightly to 90.9% (95% CI: 87.7–94.1%) and did not vary significantly by age groups, working status, or recall of previous EPI immunization. After a 3-dose series, 95.9% (95% CI: 93.7–98.1%) achieved seroprotection against diphtheria (Table 1). Of the 319 participants, 13 (4.1%) had a DAT level of less than 0.01 IU/mL after one dose. Two participants (0.6%) and one (0.3%)
321 received 1 dose 4-8 weeks
3. Results
16 Baseline DAT ≥ 1 IU/mL 2 Drop-out
303 received 2 doses A total of 160 healthcare workers and 161 non-healthcare workers were enrolled, of whom, 13 (8.1%) and 57 (35.4%) respectively were male. None of them had a history of recent travel to provinces with diphtheria outbreaks and only one reported a previous diphtheria disease exposure. One hundred eighty-eight (58.6%) recalled that they had already received vaccines in the EPI program, but none could provide a vaccination record.
6-12 months
161 DAT ≥ 1 IU/mL
142 received 3 doses Fig. 1. The timing and numbers of participants receiving one, two, and three doses of reduced-diphtheria-tetanus toxoid vaccine (Td).
Please cite this article as: P. Suntarattiwong, W. P. Vandepitte, P. Singhamatr et al., Seroprotection rate in adults after 1-dose, 2-dose, and 3-dose series of a reduced-diphtheria-tetanus toxoid vaccine (Td) during a diphtheria outbreak in Thailand, Vaccine, https://doi.org/10.1016/j.vaccine.2020.01.040
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.047– 306 95.9 (93.7–98.1) 290 90.9 (87.7–94.1)
90.9 (86.7–95.0) 91.0 (86.0–95.9)
.357 92.4 (88.2–96.6) 89.4 (84.6–94.2)
Adverse event
.971
97.9 (95.8–100) 93.2 (88.9–97.6)
.751 95.6 (92.3–98.8) 96.3 (93.3–99.2)
.108 .123
100 92.4 (86.4–98.4) 96.2 (91.9–100) 95.1 (90.2–99.9) (92.0–100) (78.3–93.9) (81.4–95.8) (86.8–98.4) 96.3 86.1 88.6 92.6
2-dose series (95% CI)§
Table 2 Solicited adverse events after the first, second, and third dose.
–
–
§
104 32.6 (27.4–37.8) Number with seroprotection Percentage
Proportions shown are row percentages. * p-value from univariate analysis. Multivariable analysis gave an odds ratio of 3.9 (95% CI, 0.9–16.4).
278 87.1 (83.4–90.8)
88.7 (84.1–93.3) 85.0 (78.8–91.1) – .291 Recall of previous EPI immunization (n) Yes (186) 35.0 (28.0–41.9) Unsure or never (133) 29.3 (21.5–37.2)
1st dose (n = 319)
2nd dose (n = 303)
3rd doses (n = 142)
Local reaction Any pain Grade 3 pain*
197 (61.8) 1 (0.3)
118 (38.9) 2 (0.7)
62 (43.7) 1 (0.7)
Any redness 5 cm redness
24 (7.5) 7 (2.2)
37 (12.2) 5 (1.7)
14 (9.9) 0 (0)
Any swelling 5 cm swelling
39 (12.2) 6 (1.9)
34 (11.2) 5 (1.7)
14 (9.9) 1 (0.7)
Systemic reaction Any fever 39.5 °C
8 (2.5) 0 (0.0)
6 (2.0) 0 (0.0)
4 (2.8) 0 (0.0)
Any headache Grade 3 headache*
46 (14.4) 0 (0.0)
28 (9.2) 0 (0.0)
11 (7.7) 0 (0)
Any myalgia Grade 3 myalgia*
99 (31.0) 0 (0.0)
71 (23.4) 0 (0.0)
35 (24.6) 1 (0.7)
Grade 3 = Symptoms preventing normal daily activity.
had a level of less than 0.01 IU/mL after a 2-doses and a 3-doses series respectively. The most common adverse event was pain at the injection site, which was reported in 61.8%, 38.9%, and 43.7% of participants after the first, second, and third doses respectively. Severe solicited adverse events that were considered grade 3 included symptoms that prevented normal daily activities, a temperature higher than 39.5 °C, and local swelling or erythema of more than 5 cm. After the first, second, and third doses, 0.3%, 0.7%, and 0.7% of participants reported grade 3 pain at the injection site and 2.2%, 1.7%, and 0.7% of participants reported grade 3 local swelling or erythema. None reported temperature higher than 39.5 °C or grade 3 headaches. However, one participant reported grade 3 myalgia after the third dose (Table 2). An episode of a serious adverse event related to the vaccine was reported by a healthcare worker, who developed marked pain and swelling at the injection site after the first Td dose that required hospitalization. The participant recovered completely after seven days and was suspected to have experienced a reaction from her prior immunization with two doses of tetanus toxoid approximately five years before the current Td vaccine. Due to an inadequate level of seroprotection against diphtheria, the participant decided to continue and received the second and third dose of Td with lesser pain and swelling when compared to the first dose.
.324
2.1 (1.0–4.2) Ref. .035 91.1 (86.7–95.6) 83.2 (77.4–89.1) 37.3 (29.7–45.0) 28.0 (20.9–35.0)
.014
Working status (n) Healthcare worker (158) Non–healthcare worker (161)
(35.1–57.4) (13.3–32.2) (18.9–39.4) (21.7–42.4) 46.3 22.8 29.1 32.1 Age group (n) 20–29 year (80) 30–39 year (79) 40–49 year (79) 50–59 year (81)
.074
–
.036
5.2 (1.4–19.1) Ref. 0.9 (0.4–2.2) 1.2 (0.5–3.3) 96.3 83.5 82.3 86.4 2.9 (1.4–5.8) Ref. 1.5 (0.7–3.2) 1.7 (0.8–3.9)
(92.0–100) (75.2–92.0) (73.7–90.9) (78.8–94.0)
1-dose (95% CI)§ Baseline (95% CI)§
p-value*
Multivariable analysis: Odds Ratio (95% CI)
p-value*
Multivariable analysis: Odds Ratio (95% CI)
*
Characteristics (N=319)
Table 1 The proportion of individuals with seroprotection (DAT 0.1 IU/mL) at baseline and after a 1-dose, 2-dose, and 3-dose series of Td and predictors of seroprotection.
p-value*
3-dose series (95% CI)
p-value*
P. Suntarattiwong et al. / Vaccine xxx (xxxx) xxx
4. Discussion This study demonstrated that approximately two-thirds of the Thai adult population including most healthcare workers in Bangkok were not protected against diphtheria during Thailand’s 2012– 2013 diphtheria outbreak. Furthermore, approximately one-fourth had diphtheria antitoxin levels below a minimal protective level, which made them highly susceptible to the disease [7]. Overall the baseline seroprotection rates observed here are similar to findings from a large diphtheria immunity study in Turkey, where approximately 50% of adults from 20 to 60 years old had protective immunity against diphtheria [8]. However, our baseline seroprotection rates were much lower when compared to findings from a seroprevalence study in Thailand during the same period [4]. We postulate that while our study population resided in Bangkok, their population was from remote areas of the country and as such, there might be some diversities including possible diphtheria exposures among partially immune population and repeated subclinical infection to acquire immunity, or the variation of
Please cite this article as: P. Suntarattiwong, W. P. Vandepitte, P. Singhamatr et al., Seroprotection rate in adults after 1-dose, 2-dose, and 3-dose series of a reduced-diphtheria-tetanus toxoid vaccine (Td) during a diphtheria outbreak in Thailand, Vaccine, https://doi.org/10.1016/j.vaccine.2020.01.040
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P. Suntarattiwong et al. / Vaccine xxx (xxxx) xxx
vaccination coverage both primary and booster vaccines in different areas of the country. We observed the 30–49 year age group to have the lowest rates of seroprotection, whereas the 20–29 year age group had the highest at baseline and at after one dose of Td. These are similar to findings from both of the studies previously mentioned [4,8]. A diphtheria disease and vaccination coverage survey report showed that the 30–49 year age group had probably received less than three doses of DTP during their childhood at the beginning of EPI program in Thailand [6]. This underlined the importance of primary diphtheria immunization coverage in infants, as well as a programmatic booster vaccination after childhood. Regarding the maintenance of tetanus and diphtheria immunity in Thailand, decennial boosting with Td has been recommended. Nevertheless, less than 60% of Thai adults, including the healthcare workers in this study can recall receiving a diphtheria vaccine, suggesting the need to strengthen Thailand’s adult vaccination program. Immune response was induced to a seroprotective level with one dose of Td in 87% (95% CI: 83–91%) of our study population. Evidence from the prevaccine era suggested the estimated herd immunity threshold to be between 80% and 85% vaccine coverage [7]. This implies that vaccinating 80–85% of the population could prevent people in the community from contracting diphtheria. Moreover, any possible breakthrough disease would likely be mild among immunized individuals. Therefore, from a public health perspective, a single dose of Td may be a sufficient recommendation for the general population of adults and healthcare workers during a diphtheria outbreak, which would be in agreement with the recommendations from a seroprevalence study conducted in Thailand [4] and practices during a more recent outbreak in South Africa [9]. Although no level of antitoxin confers absolute protection against diphtheria and there were reported cases of fatal diphtheria in individuals with a high level of antitoxin, it has been concluded that an antitoxin level of 0.01 IU/mL is the lowest level that provides some degree of protection in most circumstances [7]. After one dose of Td, 4% of the study population still had serum antitoxin levels below 0.01 IU/mL. This proportion was reduced to 0.6% and 0.3% after two and three doses respectively. A 2-dose series of Td could be considered for individual protection of persons at risk of exposure to diphtheria, particularly those presumedly naive to the diphtheria toxoid-containing vaccine, e.g., healthcare workers born before 1980 when DTP coverage in Thailand was less than 80% [6]. A self-reported history of previous immunization in the EPI program without documentation did not show a significant difference in seroprotection after one or two doses of Td and is not useful for vaccination planning. Regardless of vaccination status, standard post-exposure management, including antimicrobial prophylaxis, must be administered for persons in close contact with diphtheria [10]. This study has some limitations. Firstly, the data arose from convenience samples at a tertiary care hospital, therefore, might not be fully representative of the underlying population. We did not include adults older than 60 years of age and cannot be generalized to that age group. Also, the majority of our study population were female gender. However, the baseline seroprotection rate as well as after each dose were similar between male and female in our study. The adverse events following each dose also must be interpreted with caution because approximately 4% and 55% of the participants with very high antitoxin levels were excluded from receiving their second and third doses respectively. Nevertheless, adverse events after the first and second doses were very similar, despite half of the participants already having antitoxin levels above 1 IU/mL before receiving their second doses. We concluded that one dose of Td should be recommended for adults during a diphtheria outbreak, with the option for a 2-dose series for healthcare workers born before 1980. A booster vaccination program for
adults, particularly for healthcare workers against emerging vaccine-preventable diseases such as diphtheria and pertussis [11,12] must be implemented. CRediT authorship contribution statement Piyarat Suntarattiwong: Conceptualization, Methodology, Project administration, Data curation, Writing - original draft, Writing - review & editing. Warunee Punpanich Vandepitte: Conceptualization, Methodology. Pon Singhamatr: Investigation. Tawee Chotpitayasunondh: Conceptualization, Methodology, Funding acquisition, Resources. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgement We would like to thank Dr. Siraporn Sawasdivorn, the former Director of Queen Sirikit National Institute of Child Health and Ms. Thasanan Aumprasert, Hospital Infection Control Head Nurse for their support in facilitating this study. Also, we would like to thank Dr. Joshua Mott, CDC Influenza Regional Program in Bangkok, Thailand for his English language review of the manuscript. Funding This work was supported by the Department of Medical Services Research Fund, Thai Ministry of Public Health. References [1] Acosta AM, Tiwari TSP. Diphtheria. In: Ryan ET, Hill DR, Solomon T, Aronson NE, Endy TP, editors. Hunter’s Tropical Medicine and Emerging Infectious Diseases (Tenth Edition). London: Elsevier; 2020: p. 439–45. [2] Hughes GJ, Mikhail AF, Husada D, et al. Seroprevalence and determinants of immunity to diphtheria for children living in two districts of contrasting incidence during an outbreak in East Java, Indonesia. Pediatr Infect Dis J 2015;34:1152–6. https://doi.org/10.1097/inf.0000000000000846. [3] Sein C, Tiwari T, Macneil A, et al. Diphtheria outbreak in Lao People’s Democratic Republic, 2012–2013. Vaccine 2016;34:4321–6. https://doi.org/ 10.1016/j.vaccine.2016.06.074. [4] Wanlapakorn N, Yoocharoen P, Tharmaphornpilas P, Theamboonlers A, Poovorawan Y. Diphtheria outbreak in Thailand, 2012; seroprevalence of diphtheria antibodies among Thai adults and its implications for immunization programs. Southeast Asian J Trop Med Public Health 2014;45:1132–41. [5] World Health Organization. Diphtheria vaccine: WHO position paper, August 2017 - Recommendations. Vaccine 2018;36:199–201. https://doi.org/10.1016/ j.vaccine.2017.08.024. [6] Tharmaphornpilas P, Yoocharoan P, Prempree P, Youngpairoj S, Sriprasert P, Vitek CR. Diphtheria in Thailand in the 1990s. J Infect Dis 2001;184:1035–40. https://doi.org/10.1086/323453. [7] Tiwari TSP, Wharton M. Diphtheria toxoid. In: Plotkin SA, Orenstein WA, Offit PA, Edwards KM, editors. Plotkin’s Vaccines (Seventh Edition). Philadelphia: Elsevier; 2018: 261–75.e7. https://doi.org/10.1016/B978-0-323-35761-6. 00019-5. [8] Kurugol Z, Midyat L, Turkoglu E, Isler A. Immunity against diphtheria among children and adults in Izmir, Turkey. Vaccine 2011;29:4341–4. https://doi.org/ 10.1016/j.vaccine.2011.04.016. [9] Mahomed S, Archary M, Mutevedzi P, et al. An isolated outbreak of diphtheria in South Africa, 2015. Epidemiol Infect 2017;145:2100–8. https://doi.org/ 10.1017/s0950268817000851. [10] American Academy of Pediatrics. Diphtheria. In: Kimberlin DW Brady MT, Jackson MA, Long SS, editors. Red Book: 2018 Report of the Committee on Infectious Diseases. 31 ed. Itasca, IL: American Academy of Pediatrics; 2018: 319–23. [11] Sangal L, Joshi S, Anandan S, et al. Resurgence of diphtheria in North Kerala, India, 2016: Laboratory Supported Case-Based Surveillance Outcomes. Front Public Health 2017;5:218. https://doi.org/10.3389/fpubh.2017.00218. [12] Suntarattiwong P, Kanjanabura K, Laopipattana T, Kerdsin A, Paveenkittiporn W, Chotpitayasunondh T. Pertussis surveillance in a children hospital in Bangkok, Thailand. Int J Infect Diseases 2019;81:43–5. https://doi.org/ 10.1016/j.ijid.2019.01.031.
Please cite this article as: P. Suntarattiwong, W. P. Vandepitte, P. Singhamatr et al., Seroprotection rate in adults after 1-dose, 2-dose, and 3-dose series of a reduced-diphtheria-tetanus toxoid vaccine (Td) during a diphtheria outbreak in Thailand, Vaccine, https://doi.org/10.1016/j.vaccine.2020.01.040