Pertussis specific cell-mediated immune responses ten years after acellular pertussis booster vaccination in young adults
Introduction
Pertussis has been re-emerging in several industrial countries during the past years. Countries such as the USA and the United Kingdom have witnessed the resurgence of pertussis with large epidemics [1], [2]. There are several reasons for Bordetella pertussis, the causative agent of pertussis, to continue circulating. One reason is the fact that immunity against acellular vaccine wanes over time. Most of these industrial countries have used acellular pertussis (aP) vaccines since the 1990s, when aP replaced the traditional whole cell vaccines (wP) due to its higher reactogenicity. However, this change has not been able to control B. pertussis circulation. Although the mechanism behind the protection against pertussis has not been fully understood, it is believed that both humoral and cell mediated immune (CMI) responses are needed for the protection [1], [3]. Clinical trials in the 1990s indicated that antibodies against acellular pertussis vaccine antigens such as pertussis toxin (PT), fimbriae (fim) and filamentous hemagglutinin (FHA) correlate with protection [4], [5]. The acellular vaccine is known to produce high antibody titers against vaccine antigens, but the amount of antibodies decreases sharply already within a few years after the vaccination [6]. However, immunized children with low levels of antibodies might be protected [7], [8]. The cell-mediated immunity (CMI), mediated by T and B cells, has been shown to contribute to protection [7], [9]. The aP and wP vaccines differ in their T helper (Th) cell responses. Acellular vaccines are known to drive the immune responses to mixed Th2/Th1 direction whereas the wP vaccine induces Th1 type of immune reaction, which resembles more that of a natural infection [3]. Cytokine network is an essential part of the innate and adaptive immune responses. They have a notable role in immune responses after pertussis infection, as well as vaccine responses. The induction of interferon (IFN)-γ production by Th1 cells is important for the recovery from B. pertussis infection [10]. Similarly to infection, the whole cells vaccine induces high IFN-γ secretion, whereas the acellular vaccine does so only faintly [3]. More recently, Th17 cells have been found to mediate the protection after acellular vaccination in mice. Additionally Th1 and Th17 immunity seems to be more efficient in protection against pertussis [11].
Due to the rapid waning of humoral immune response after acellular vaccination, it is important to search for other possible surrogates of protection. The aim of this study was to investigate CMI responses before and one month after a second booster vaccine in young adults, who had received a diphtheria, tetanus, acellular pertussis (dTpa) booster vaccine ten years previously. Cytokine determination was performed to investigate several types of cytokines; the Th1-type (IFN-γ, IL-2, TNF-α, IL-12), Th2-type (IL-4), Th17-type (IL-17), pro-inflammatory (IL-8 and IL1B), regulatory IL-10 and inflammatory IL-6.
Section snippets
Cohort
The initial study started in 1997, Turku, Finland. Five hundred and ten adolescents, aged 11–13 years, were recruited to receive a single booster dose of acellular pertussis vaccine (Boostrix, GlaxoSmithKline). The cohort was followed-up at 3, 5 and 10 years after the booster vaccination. At the 10-year follow-up, the same cohort was invited to receive an additional dTpa booster vaccine and 82 subjects enrolled in the study [12]. From the ten-year follow-up, whole blood samples were collected
Proliferation assay
Proliferative responses from 57 subjects are described in Table 1. A significant increase was noticed in the geometric mean value (GMV) of the absolute cell count (cpm), as well as in the SI against all pertussis antigens after the vaccination (Table 1). Four subjects (7%) had a low response (SI < 4) to all antigens before vaccination. Of these, three became positive after vaccination. One subject had positive SI only against FHA (SI = 4.6). The geometric mean value of the SI was barely over the
Discussion
A high level of antibodies is known to confer protection against pertussis. However, antibodies decay within years after acellular vaccination. The decreasing antibodies are one of the factors contributing to large outbreaks noticed worldwide [6], [15]. This highlights a clear need for improved understanding of factors affecting vaccine-induced immunity.
Our results indicate that 10 years after the first booster vaccination, from subjects with diminished IgG antibodies against PT, 40% still had
Conclusions
Our results indicate that CMI persists even after antibodies have decayed, and acellular vaccine enhances the CMI response. However, it should be noted that humoral immunity was not found to correlate with CMI, and each type of response can be active regardless of the other. Further studies are needed to illustrate what factors cause the low production of some important cytokines.
Conflict of interest statement
Olivier Van Der Meeren is an employee of GlaxoSmithKline Vaccines. All other authors: No reported conflicts.
Acknowledgment
Päivi Haaranen and Tuula Rantasalo are acknowledged for their excellent technical support.
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