Welcome to Part 2 of Jenner’s Legacy. Following on from my discussion of Jenner’s pioneering work in smallpox vaccination, here I will explain why it’s so difficult use this approach to develop ideal vaccines for influenza and dengue.
Inoculating against Influenza
Influenza is a viral disease that we are all too familiar with. Although we often think of the influenza virus as a single pathogen, the virus is in fact extremely varied. There are two main types of influenza viruses that infect humans, influenza A and B, and these are further characterized into different subtypes and lineages. Within each subtype, there are also numerous strains. A wide variety of influenza strains exist because the influenza virus is continuously evolving through an ongoing process of mutations, which alters its surface proteins. New influenza strains also emerge when two or more viruses present in a single host recombine their viral segments to generate a dramatically different strain, such as the most recent 2009 pandemic H1N1 strain.
The ability of the influenza virus to constantly mutate and change allows it to fool the body’s natural immune response. Our body’s immune system combats the influenza virus by producing antibodies that bind to the virus’s surface proteins. If these surface proteins were constant from one strain of influenza to the next, Jenner’s methodology for vaccines would work brilliantly with the power of immunological memory, saving millions from the horrors of flu season every year. Unfortunately, it is precisely the variable surface proteins to which majority of the antibodies of the immune system bind.
However, that does not mean that antibodies produced from an influenza vaccination are entirely without use. Antibodies produced in response to a particular strain of influenza are effective in protecting the body from future infections of that particular strain and similar strains. In fact, this effect is the primary driving force behind the modern influenza vaccine that millions take each influenza season. Every one to three years, the influenza vaccine is reformulated to contain the strains that are predicted to circulate in the upcoming influenza season. When the vaccine strains match the circulating strains, there is good protection against influenza infections. However, the predictions of which strains will circulate in a particular influenza season are not always accurate, and they cannot account for the unexpected emergence of recombined strains. When mismatches between vaccine strains and those that infect in a given season occur, the vaccine does not provide the desired level of protection. Hence, while the current influenza vaccine has tremendously reduced influenza infections and deaths, it is not yet an ideal vaccine that can provide complete coverage against all influenza strains.
Mounting a defense against dengue
Similarly, the dengue virus is another infectious agent characterized by many different virus types. There are four distinct serotypes of dengue viruses (DENV1 to DENV4) that share 60–80 per cent similarity to each other. To provide coverage against all 4 serotypes of the virus, the simplest strategy for a vaccine is to include all four serotypes in the vaccine formulation. Indeed, Dengvaxia, the first dengue vaccine to be approved for human use in Mexico, Philippines and Brazil, employs this approach. While Dengvaxia provides strong protection against severe dengue, it is far from a perfect vaccine. Efficacy against each serotype is varied, with the lowest efficacy seen for DENV2, at only 42 per cent. Furthermore, due to lower efficacy in the young and old, the vaccine is only approved for persons between the ages of 9 and 45, leaving vulnerable age groups without any protection. Scientists are still trying to determine why such an approach to dengue is not entirely effective and why Dengvaxia fails to be the one-stop solution for dengue.
Even though the diversity of the dengue virus poses some challenges for dengue vaccine development, it is really the nature of our natural immune responses against dengue that have scientists truly stumped. Upon first infection with any one of the four serotypes of dengue, our immune system gets activated and produces antibodies that bind not only to the infecting serotype but also the other three. Referred to as cross-reactive antibodies, these kinds of antibodies against viruses are generally beneficial as they can provide a wide breadth of protection against future infections with different strains. However, this is not the case with the dengue virus. For reasons still unclear to scientists, cross-protection for the other serotypes is only short-term and life-long immunity is achieved only against the infecting serotype, but not the other three serotypes. Further, previous infection with dengue actually puts a person at risk of having more severe dengue upon secondary infections with different serotypes! This is a significant problem in regions where dengue is endemic and individuals are often infected more than once. Scientists believe that although normally, antibodies with viruses bound are taken up by innate immune cells for the viruses to be destroyed within the cell, during a secondary dengue infection, cross-reactive antibodies weakly bound to dengue virus actually serve to facilitate viral entry into the immune cells, where the virus replicates and increases the level of infection. Manipulating our immune responses to prevent such a phenomenon will be crucial in reducing the severity of secondary infections with and is currently a vibrant area of investigation.
Moving beyond Jenner
While Jenner’s insights were brilliant and have revolutionized modern immunology, his straightforward approach to vaccination does not work for all infectious agents and we have many infectious diseases today that remain ‘unsolved’. Research on developing effective vaccines must now focus on rational vaccine design tailored to the complexities and nuances of a given infectious agent. Vaccine formulations can no longer be restricted to contain solely dead or weakened whole viruses or bacteria. Instead, scientists must make informed decisions by identifying the components of disease-causing agents that are most relevant for our immune system to recognize and develop long-lasting memory. For instance, to get ahead of the ever-changing influenza virus, scientists are trying to reinvent the influenza vaccine by directing their research efforts on those vital viral proteins that do not mutate from strain to strain, but instead remain constant in all influenza types. In the case of dengue, while several other vaccine formulations are being tested in clinical trials, research efforts are focused on bridging our knowledge gaps on the interaction between our immune system and the dengue viruses.
My research is focused on furthering our understanding of the characteristics of human antibody responses during primary and secondary dengue infections. There is still so much we don’t understand about human immune cell responses after a dengue infection. As we learn more about how our immune system responds to the dengue virus and what is needed to acquire long-term protection, we can uncover strategies that can be leveraged during vaccine design. And so, scientists like myself will continue to work at finding the answers to the problems posed by disease-causing agents like the influenza and dengue viruses. Hopefully, our answers will come sooner rather than later and we can rid the world of two more infectious diseases.