The delicate balance in genetically engineering live vaccines

Abstract

Contemporary vaccine development relies less on empirical methods of vaccine construction, and now employs a powerful array of precise engineering strategies to construct immunogenic live vaccines. In this review, we will survey various engineering techniques used to create attenuated vaccines, with an emphasis on recent advances and insights. We will further explore the adaptation of attenuated strains to create multivalent vaccine platforms for immunization against multiple unrelated pathogens. These carrier vaccines are engineered to deliver sufficient levels of protective antigens to appropriate lymphoid inductive sites to elicit both carrier-specific and foreign antigen-specific immunity. Although many of these technologies were originally developed for use in Salmonella vaccines, application of the essential logic of these approaches will be extended to development of other enteric vaccines where possible. A central theme driving our discussion will stress that the ultimate success of an engineered vaccine rests on achieving the proper balance between attenuation and immunogenicity. Achieving this balance will avoid over-activation of inflammatory responses, which results in unacceptable reactogenicity, but will retain sufficient metabolic fitness to enable the live vaccine to reach deep tissue inductive sites and trigger protective immunity. The breadth of examples presented herein will clearly demonstrate that genetic engineering offers the potential for rapidly propelling vaccine development forward into novel applications and therapies which will significantly expand the role of vaccines in public health.

Early molecular correlates of adverse events following yellow fever vaccination

“…immune response is directly correlated with the robustness of adaptive immune response suggests that potent vaccines are inherently reactogenic; the innate immune response could drive both vaccine immunogenicity and AEs (10). If this is true, then immunogenicity and reactogenicity are a molecularly intertwined yin-yang of vaccination; AEs are undesired but necessary collateral effects of potent vaccines.…”

Typhoid Fever as a Challenge for Developing Countries and Elusive Diagnostic Approaches Available for the Enteric Fever

“…Three types of Salmonella vaccines are licensed: the oral live attenuated Salmonella typhi Ty21a vaccine and the parenteral Vi capsular polysaccharide antigen, either unconjugated or conjugated to tetanus toxin [105][106]. Vi capsular Polysaccharide (Vi-PS) vaccines confer protection approximately 7 days post immunization.…”

Impfungen bei Immundefekten/Immunsuppression – Expertenstatement und Empfehlungen

“…Das heißt, dass die Attenuierung (die z. B. auf Inaktivierung von Toxinbildung oder anderen Virulenzfaktoren beruht) gerade so weit gehen soll, dass sie unerwünschte Reaktionen verhindert, aber nicht so weit, dass sie die Immunogenität der Impfung zu sehr beeinträchtigt [3]. Dieses subtile Gleichgewicht wird jedoch für gesunde Probanden ermittelt und muss daher auf immunsupprimierte Patienten nicht zutreffen [4].…”