The discovery of influenza A virus in 1933 followed an intensive search for the pathogen responsible for the 1918–1919 pandemic. This breakthrough led to the development and production of egg-grown, whole-virus, formalin-inactivated influenza vaccines that were shown to be effective in military recruits. They were never formally tested in the elderly, in whom influenza is most severe, or in young, immunologically naive children, in whom attack rates are highest. Whole-virus vaccines were replaced in the late 1970s by split and subunit vaccines that were far less reactogenic, particularly in young children. However, with the remergence of H1N1 virus during the 1970s, it soon became clear that split and subunit vaccines were less immunogenic than whole-virus vaccines in immunologically naive people. This finding was again observed in man during recent trials of H5 and H9 subtypes of avian influenza, but it evidently mattered little during the 1980s and 1990s as the principal targets of immunization were the elderly and those with comorbidities, who were already primed by H1N1 and H3N2 strains of influenza A and B. Trials of live-attenuated influenza vaccines began during the 1970s, but the path to vaccine licensure has been slow, and live influenza vaccines currently have a limited role.
Inactivated influenza vaccines are given to approximately 350 million people annually worldwide – a figure far short of the WHO targets and national recommendations, particularly in high-risk under-65-year-olds, and contrasting sharply with the high uptake of pediatric vaccines. While in economically deprived countries it is clear that limited resources should be targeted preferentially at childhood immunization programs and conditions such as diarrheal disease, malaria, tuberculosis and HIV, the social and economic burden of influenza in economically developed countries justifies widespread use of effective influenza vaccines. So why isn’t this happening?
In part, it is because the most widely used inactivated influenza vaccines – plain (i.e., nonadjuvanted) subunit (purified hemagglutinin and neuraminidase) and split (disrupted influenza virion) egg-grown vaccines have substantial limitations. First, and perhaps most importantly, vaccine failures occur in the elderly, but we have no knowledge of how often this occurs or the extent of protection they really afford in the frail elderly. That said, vaccine effectiveness studies of the elderly generally point to important benefits. Current inactivated vaccines are poorly immunogenic in young children. They do not provide as broad or durable response as required and, because of antigenic drift, must be given annually. Occasionally, there are mismatches between the vaccine and wild-type strains, resulting in loss of protection. The dependence on eggs to grow influenza virus poses manufacturing problems that occasionally result in delays in distribution and potential shortages of vaccine. Moreover, in the event of a pandemic, the necessary number of high-quality fertile hens’ eggs, and the capacity of manufacturers to process them, is unlikely to match global needs. These are just some limitations of the most widely used influenza vaccines. Importantly, they are well recognized and are being addressed.
Some significant developments have already occurred – notably the development of oil-in-water adjuvants and the development of cell-culture vaccines. Others are occurring and are in early stages of development and evaluation. Thus, it is timely to review the extent of developments and current progress. This issue of Expert Review of Vaccines provides the reader with an excellent overview. It takes time to develop and test new vaccines and bring them to the market. Some are likely to fall by the wayside. Meanwhile, it is imperative that the available vaccines and the newer adjuvanted vaccines are compared in clinical trials and used more widely. After all, some protection is better than none, and influenza vaccines offer good value for money.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.