Immunogenicity and safety of a tetanus-diphtheria vaccine and a 13-valent pneumococcal conjugate vaccine after concomitant vaccination in ≥ 50-year-old adults

Vaccination is the most effective strategy to prevent diverse infectious diseases. Actually, the World Health Organization (WHO) estimates that vaccinations avert 2–3 million deaths per year [1]. In adults, several vaccines are recommended based on age if the vaccine has not been received before, and there is a lack of evidence of past infection: influenza; measles, mumps and rubella (MMR); varicella; human papillomavirus (HPV); tetanus-diphtheria (Td); tetanus, diphtheria and acellular pertussis (Tdap); and pneumococcal vaccination. In addition, adults should be vaccinated with a variety of vaccines, including those for hepatitis A virus (HAV), hepatitis B virus (HBV), Haemophilus influenzae type B (Hib) and meningococcal, based on underlying medical conditions. Thus, adults frequently visit outpatient clinics to receive two or more kinds of vaccines at the same time, as multiple vaccines are given concomitantly during routine pediatric immunizations.

Actually when a patient visits a vaccination clinic, Td and the pneumococcal vaccines are commonly administered at the same time. Pneumococcal vaccines are recommended for chronically ill patients and the elderly aged ≥65 years, while a booster dose of the Td vaccine is required every 10 years from the age of 11–12 years due to waning immunity [2, 3]. Tetanus can be prevented only by vaccination because immunity against this disease is not naturally acquired [4, 5]. Herd protection cannot be induced because tetanus is not person-to-person transmitted.

The development of polysaccharide-protein conjugate technology markedly improved vaccine immunogenicity and enabled the efficient prevention of diverse fatal infectious diseases by encapsulated pathogens such as Hib, Neisseria meningitidis, and Streptococcus pneumoniae. However, there are concerns about immune interference when multivalent conjugate vaccines are co-administered with other vaccines [6]. There are many kinds of carrier proteins: tetanus toxoid (TT), diphtheria toxoid (DT), CRM₁₉₇ (non-toxic variant of DT), OMP (complex outer-membrane protein mixture from N. meningitidis), and non-typeable H. influenzae-derived protein D. Depending on the type of carrier proteins and co-administered antigen doses, the degree of immune interference may vary.

In this study, we aimed to evaluate the immunogenicity and safety of the Td vaccine and 13-valent pneumococcal conjugate vaccine (PCV13) after concomitant administration in adults aged 50 years and older.

This study is reported according to CONSORT (Consolidated Standards of Reporting Trials) guidelines.

It is very common and efficient to administer two different kinds of vaccines simultaneously for a patient when visiting a clinic. Nevertheless, there are some concerns whether it is safe to administer two vaccines at the same time and whether they can induce sufficient immunity for each vaccine antigen. This study shows that concomitant administration of Td and PCV13 is safe and induces non-inferior immune responses to both vaccine antigens compared to each vaccine alone. Although the pre-vaccination anti-tetanus titer was rather higher in Group 3 (Td alone) compared to Group 1 (PCV13 + Td), seroprotection rates were comparable between the two groups at day 0 (pre-vaccination) and day 28 (post-vaccination; Table 2).

However, an interesting finding in the present study was that the Td vaccine alone induced high IgG anti-tetanus antibody titer (≥ 0.5 U/mL) in a greater proportion than when it was given simultaneously with PCV13. As reported previously, bystander interference might decrease the immune response to co-administered vaccine antigens through competition for limited resources within the lymph nodes and induction of regulatory T-cells [6, 12]. Among carrier proteins, CRM₁₉₇ was suggested to trigger regulatory T-cells, thereby decreasing memory B-cell responses [6]. Although less likely to cause carrier-induced epitopic suppression (CIEP) on polysaccharide antigens compared to TT, CRM₁₉₇ is more likely to induce bystander interference [6, 12]. Multi-valent PCVs with ≥15 serotypes are under development, and they may contain higher doses of CRM₁₉₇ and a larger amount of polysaccharide antigens [13, 14]. Thus, these extended serotype-covering multivalent PCVs might be able to decrease the immune response to co-administered Td or Tdap by bystander interference. Further studies are warranted to better clarify the possible immune interference when these new vaccines are introduced.

On the other hand, co-administration of Td and PCV13 elicited substantially high OPA titers for all four pneumococcal serotypes and induced a superior immune response for serotype 1 pneumococci compared to PCV13 alone in this study (Table 3). It has been suggested that CRM₁₉₇ might induce better immune responses when co-administered or primed with DT [6, 12]. In fact, in previous studies, the response against CRM₁₉₇-conjugated Hib was enhanced with co-administration of DT, suggesting immune enhancement by DT-induced T-helper cells [10, 15]. The CRM₁₉₇-induced CIES effects on polysaccharide antigens may be mitigated by co-administered DT. However, this immune-enhancing effect is not consistently reported in other studies, and observed in a single serotype in the present study. Careful interpretation will be necessary and further research is required. In the studies by Tashani et al., sequential or co-administration of Tdap and PCV13 were compared; OPA titers for PCV13 were significantly higher among concomitant Tdap and PCV13 recipients compared to sequential Tdap and PCV13 recipients [16, 17]. They suggested that prior exposure to Tdap might suppress immune responses to PCV13. Thus, either Td or Tdap vaccination should be scheduled concomitantly or later than PCV13 administration.

As for the safety profile, co-administration of Td and PCV13 is safe and well tolerated. Although PCV13 induced more frequent local pain, concomitant administration of Td and PCV13 had no additive effects on adverse events. The incidences of local and systemic adverse events were comparable to those in previous reports [18‐21].

There were some limitations in this study. First, this study was limited by the restricted number of pneumococcal antigens that could be tested (4 of 13). Second, insufficient information was available on previous Td vaccination. Although we only included subjects without Td vaccination in recent 10 years, the number of prior Td vaccination might affect the immune responses against Td antigens.

When two or more vaccines are administered concurrently, the main concern regarding vaccine interaction is the safety and clinical relevance for individual protection. In this study, the Td vaccine and PCV13 were safe and immunogenic without significant immune interference when administered concomitantly.