Why are vaccines against many human viral diseases still unavailable; an historic perspective?

The number of new and improved human viral vaccines licensed in recent years contrasts sharply with what could be termed the golden era (1955-1990) when vaccines against polio-, measles, mumps, rubella, and hepatitis B viruses first became available. Here, we attempt to explain why vaccines, mainly against viruses other than human immunodeficiency virus and hepatitis C virus, are still unavailable. They include human herpesviruses other than varicella-zoster virus, respiratory syncytial and most other respiratory, enteric and arthropod-borne viruses. Improved oral poliovirus vaccines are also urgently required. Their unavailability is attributable to regulatory/economic factors and the properties of individual viruses, but also to an absence of relevant animal models and ethical problems for the conduct of clinical of trials in pediatric and other critical populations. All are portents of likely difficulties for the licensing of effective vaccines against emerging pathogens, such as avian influenza, Ebola, and Zika viruses.

Estimating the fitness advantage conferred by permissive neuraminidase mutations in recent oseltamivir-resistant A(H1N1)pdm09 influenza viruses.

Oseltamivir is relied upon worldwide as the drug of choice for the treatment of human influenza infection. Surveillance for oseltamivir resistance is routinely performed to ensure the ongoing efficacy of oseltamivir against circulating viruses. Since the emergence of the pandemic 2009 A(H1N1) influenza virus (A(H1N1)pdm09), the proportion of A(H1N1)pdm09 viruses that are oseltamivir resistant (OR) has generally been low. However, a cluster of OR A(H1N1)pdm09 viruses, encoding the neuraminidase (NA) H275Y oseltamivir resistance mutation, was detected in Australia in 2011 amongst community patients that had not been treated with oseltamivir. Here we combine a competitive mixtures ferret model of influenza infection with a mathematical model to assess the fitness, both within and between hosts, of recent OR A(H1N1)pdm09 viruses. In conjunction with data from in vitro analyses of NA expression and activity we demonstrate that contemporary A(H1N1)pdm09 viruses are now more capable of acquiring H275Y without compromising their fitness, than earlier A(H1N1)pdm09 viruses circulating in 2009. Furthermore, using reverse engineered viruses we demonstrate that a pair of permissive secondary NA mutations, V241I and N369K, confers robust fitness on recent H275Y A(H1N1)pdm09 viruses, which correlated with enhanced surface expression and enzymatic activity of the A(H1N1)pdm09 NA protein. These permissive mutations first emerged in 2010 and are now present in almost all circulating A(H1N1)pdm09 viruses. Our findings suggest that recent A(H1N1)pdm09 viruses are now more permissive to the acquisition of H275Y than earlier A(H1N1)pdm09 viruses, increasing the risk that OR A(H1N1)pdm09 will emerge and spread worldwide.