“It’s time to close the book on infectious diseases, declare the war against pestilence won, and shift national resources to such chronic problems as cancer and heart disease” [1
]. Contrary to this infamous statement, long misattributed to the former US Surgeon General Dr. William H. Stewart, and despite advances in healthcare and technology, we remain extremely vulnerable to the threat of communicable diseases. In the last ten years alone, we have experienced the pandemic spread of swine-origin H1N1 influenza, the West African Ebola epidemic, the resurgence of yellow fever, the Zika virus emergency, and the return of a global coronavirus threat [2
]. With the continued emergence and re-emergence of new and current viral pathogens, it is imperative that we continue to design new strategies to combat their spread and prevent human disease.
Among the various methods to impede viral transmission, vaccines are widely heralded as one of the most effective medical interventions. Indeed, since the pivotal discovery by Edward Jenner over two hundred years ago, vaccination has seen tremendous success in reducing the burden of viral diseases such as polio, yellow fever, measles, mumps, rubella, hepatitis A, hepatitis B, and influenza [7
]. However, perhaps the greatest testament to their success is the eradication of smallpox in 1980 [9
]. According to the World Health Organization (WHO), vaccination now saves over 2.5 million lives annually and prevents even more cases of illnesses and serious disabilities [10
]. Moreover, taking into account both treatment costs and lost productivity due to death and disability, vaccines are estimated to provide billions of dollars’ worth in cost savings between 2011 and 2020 [11
]. In addition, at high enough coverage, vaccination can impart both individual and community protection in the form of herd immunity, safeguarding those who are legitimately incapable of receiving immunization. On the other hand, reduced vaccine coverage threatens to cause a resurgence of vaccine-preventable diseases, including measles, mumps, and pertussis [12
]. With such accolades, vaccination is widely considered as the crowning achievement of public health, and the WHO touts it as the most cost-effective method to prevent infectious diseases. Given their remarkable track records, vaccination is likely to remain a cornerstone of antiviral strategies, especially with the increasing prevalence of epidemic viral diseases.
The last few decades have witnessed remarkable advances in vaccine design and development, with new and innovative technologies redefining our approaches to vaccine production. Nevertheless, one particular class of vaccines has withstood the test of time and has remained in use ever since the advent of immunization: the live-attenuated vaccines (LAVs). Comprised of living but attenuated microorganisms, this group, which also includes replication-competent viral vectors, retains the capacity to replicate in vivo but does not cause disease in humans. Due to their ability to mimic a natural infection and activate innate immune responses, LAVs are able to induce long-lasting, robust cellular and humoral immune responses without the need for adjuvants [13
]. This provides an added advantage over their inactivated counterparts, which often require adjuvants to stimulate innate immune responses for the induction of adaptive immune responses. Active viral replication within cells enables antigen processing via major histocompatibility complex (MHC) class I, which is pivotal in activating cytotoxic CD8+ T-cells that facilitate clearance of virus-infected cells [14
]. Furthermore, LAVs contain a repertoire of antigens similar to the wild-type organism, allowing them to present all epitopes in their native conformation to antigen-presenting cells [15
]. Given their potential in activating robust CD8+ and CD4+ responses, polio, recombinant vesicular stomatitis virus (VSV), recombinant adenovirus, and attenuated measles vaccines have also been proposed as potential viral vectors for the delivery of tumor antigens [16
One of the greatest challenges for the development of LAVs is to ensure that the vaccine is safe and does not cause serious adverse events. Moreover, they should not replicate in vectors to prevent viral transmission, and caution must be taken to ensure that the attenuated viral strains do not revert to a wild-type virus. Therefore, to ensure the safety of LAVs, there is usually a tendency to select LAV candidates with limited replicative potential in order to reduce the risk of adverse events. However, it is also critical to ensure that LAV candidates are not over-attenuated so as to induce sufficient innate and adaptive responses necessary for vaccine efficacy. Vaccine immunogenicity and efficacy, however, are difficult to assess in animal models and may not correlate with clinical efficacy. An example is the Dengvaxia®
vaccine manufactured by Sanofi Pasteur, which generated protective antibody and T-cell responses against all dengue virus serotypes in non-human primates, but in phase II and III clinical trials, only low to modest efficacy was observed against DENV serotype 1 and 2 [18
]. Controlled human infection model (CHIM) trials are now considered for evaluation of vaccine candidates but the ethical, laboratory, scientific, and governance issues should be carefully managed [20
With an anticipated increase in the demand for vaccines to control viral epidemics and high-endemicity of virus infection worldwide, the presence of pre-existing antibodies caused by infection or vaccination with an antigenically similar virus may influence the outcome of LAV immunogenicity and efficacy. Thus, vaccines that are administered to the adult population will have to consider the role of pre-existing immunity on vaccine efficacy. Conversely, it is critical to determine whether the administration of LAV generates sufficient antibody responses that protect against wild-type virus infections and not cause worse disease outcomes. For vaccines that are administered to neonates, the presence of passively acquired maternal antibodies within the first six months may also interfere with vaccination [21
]. The potential effects of pre-existing antibodies on LAV and virally vectored antigens will hence be the focus of this review. In this review, we examine the scenarios in which pre-existing antibodies can either enhance or inhibit LAV efficacy, as well as the underlying mechanisms involved. A better understanding will allow us to tailor our vaccination schedules or vaccine doses, to ensure that LAV efficacy will not be compromised by the presence of pre-existing immunity.