The Challenges of Neutralizing Influenza and the Quest for a Universal Vaccine

Figure 1: Influenza structure. Source: http://www.cdc.gov/flu/images.htm

Figure 1: Influenza structure.
Source: http://www.cdc.gov/flu/images.htm

Imagine you are beginning the second semester of your freshman year at Washington University. As you return to class in the winter, you very quickly become sick from a terrible virus. Student Health Services is overwhelmed, with little or no time to help you, as the virus has made over a third of the students on campus ill. The disease continues to spread over the next three years. Some students eventually heal, but some are not so lucky. By the time you are a senior, 350 students have died.

This was the reality of the 1918-1920 Spanish Flu. A particularly devastating flu pandemic, with no drugs or vaccine to treat it, affected 500 million people and killed between 50 and 100 million [1]. In 1942, the first influenza vaccine was developed, and while the world hasn’t seen another outbreak as disastrous as the Spanish flu, humanity has been hit hard by three more pandemics: the Asian Flu in 1957, the Hong Kong Flu in 1968, and most recently, the Swine Flu in 2009. The flu season does not have to be a full-blown pandemic to be a public health crisis; every year, the virus kills around 250,000 people, of whom 80-90 percent are at least 65 years of age [2][3]. The 2016-2017 flu season has begun, and while not everybody’s life will be seriously threatened, many groups of people  — such as those over 65 and under 5 years old, those who suffer from asthma, heart disease, chronic lung disease, diabetes, and a wide range of other disabilities — are always at risk of developing serious complications from the flu [4]. The influenza vaccine is the strongest line of defense against the annual flu, but it is far from perfect, as it is not like most other vaccinations. Compared to a measles vaccine, the flu vaccine does not elicit as strong of an immune response, is less effective, and does not provide lifelong protection. The circulating flu virus is different every year, making the universal, fully protective influenza vaccine a very challenging goal.

The Structure of Influenza Virus

A flu virus is a roughly spherical, with eight RNA strands enclosed inside and about 500 proteins sticking out [5]. These proteins include hemagglutinin (HA) and neuraminidase (NA) (See Figure 1). A virus gets its name based on which of the 18 types of HA and 11 types of NA proteins are attached. For example, the H3N2 virus consists of HA protein type 3, and NA protein type 2. The HA and NA proteins are the keys to facilitating the release of the eight viral RNA strands into human cells. Once released, the RNA replicates repeatedly, and goes on to infect neighboring cells, and the disease begins.

Influenza Mutation

Figure 2A: Antigenic Drift Process. Figure 2B: Antigenic Shift Process. Source: https://healthhearty.com/antigenic-drift-vs-antigenic-shift

Figure 2A: Antigenic Drift Process. Figure 2B: Antigenic Shift Process. Source: https://healthhearty.com/antigenic-drift-vs-antigenic-shift

Every year, the globally circulating flu virus mutates through two processes: antigenic drift and antigenic shift (See Figures 2A, 2B). Antigenic drift occurs when mutations in the viral strains accumulate over time. In all likelihood, a single mutation will not alter the virus drastically, and it will still be recognizable to antibodies in the body (this is called cross-protection), but when changes add up over time, the virus becomes significantly different, and the human body is no longer protected from that circulating strain [6]. Antigenic shift is rarer, and occurs when two different flu viruses combine with each other inside the same host cell to form a new hybrid flu virus strain. These changes in the flu virus are much more dramatic, as the composition of the resulting flu virus is altered far more than it would be from a year of antigenic drift. Antigenic shifts have been responsible for the Asian Flu, Hong Kong Flu, and Swine Flu scare of 1976 [7].

Development of the Annual Vaccine

To stay one step ahead in neutralizing a rapidly mutating virus, we need a rapidly updating vaccine. Every year, the World Health Organization (WHO) receives data from over 100 national influenza centers around the world, each of which examines thousands of flu strains that have infected patients [8]. The WHO uses the data it gathers to predict which flu strains are likely to predominate in the coming year, and upon making a prediction, begin growing the strains for the vaccine. The vaccine usually contains one H1N1 strain, one H3N2 strain, and one influenza B strain (a trivalent vaccine). The growth mostly takes place inside chicken eggs, but can also occur inside mammalian cells or be produced with recombinant technology. Since the vaccine takes a long time to grow, and millions of chicken eggs or mammalian cells are required to provide enough for the entire country, the WHO has to make their prediction as early as nine months in advance [9]! In other words, the flu season is likely to still be going on when the prediction for next year’s virus has been made, and the preparation of next year’s vaccine has begun. The need to make a prediction so early on, when there may be significant antigenic drift or shift in the coming months, means that the flu strains in the vaccine often do not match the strains that circulate the following winter. Every 2-8 years on average, antigenic drift produces a virus that does not match the strains of the previous vaccine. It is not easy to predict when this mismatch will occur or which new vaccine strains need to be substituted in and out. When a mismatch in any of the three viral strains creates an inadequate vaccine, (See Table 1, next page), the flu season can be harsh and unforgiving.

Table 1: Statistics for influenza VE (vaccine effectiveness) by year, with a 95% CI (Confidence Interval). Source: http://www.cdc.gov/flu/pdf/professionals/vaccination/vaccine-effectiveness-table-2016.pdf

Table 1: Statistics for influenza VE (vaccine effectiveness) by year, with a 95% CI (Confidence Interval). Source: http://www.cdc.gov/flu/pdf/professionals/vaccination/vaccine-effectiveness-table-2016.pdf

Recent Progress in Vaccine Technology

Figure 3: The intradermal flu shot is a much shallower injection than the conventional intramuscular shot Source: http://www.bangkokpost.com/print/303972/

Figure 3: The intradermal flu shot is a much shallower injection than the conventional intramuscular shot
Source: http://www.bangkokpost.com/print/303972/

Developments in flu vaccine technology have been greatly boosted over the past decade thanks to tremendous innovations in computing technology [10]. Dr. Steven Lawrence, an infectious disease specialist at Washington University School of Medicine, commented that such technological breakthroughs have paved the way for better vaccines. “The ability to be able to sequence viruses very quickly and easily now certainly has aided the process,” Lawrence remarked. “The ability to be able to sequence viruses very quickly and easily now…the computing power to be able to map out some of these epitopes, the ability to determine the actual crystal structure of the proteins within the flu virus…these technologies that have really exploded in the last decade and made things much faster and much cheaper to investigate are the tools that are allowing these new approaches to move forward [with flu vaccine development] pretty quickly.”

Some innovations have improved the vaccine’s strength in older people, through higher doses and adjuvants. Some vaccines are now made without using chicken eggs to avoid the risk of allergic reactions. New flu shot alternatives, such as the nasal spray and intradermal needle (See Figure 3), can be easier to administer to children or those with a fear of needles. A recently developed quadrivalent vaccine provides protection from two separate strains of influenza B. Lawrence calls these advances “tiny increments” of improvement, albeit much larger than any development that had occurred for forty years prior. Given the scope of the public health crisis caused by the flu every year, small innovations can certainly make large differences. However, we may see larger improvements — Lawrence hopes — in the next decade. We may manufacture a vaccine that consistently provides 95+ percent protection. Perhaps we will see a vaccine that can keep the body protected for multiple years at a time. The ultimate goal, of course, would be a vaccine that does both; one that provides full protection and is long lasting, perhaps even life-lasting: the “Universal Influenza Vaccine.”

Future Progress: The Potential of a Universal Influenza Vaccine

One major goal for epidemiologists and public health workers is to develop an influenza vaccine, capable of protecting against any and all possible flu viruses, and potentially lasting for multiple years at a time, if not a lifetime. By the current methods, this is impossible because of the constantly mutating strains. But what if there were a way to target a region of the influenza virus that does not change from year to year?

Prospects

Figure 4: The structure of HA, showing its head and more conserved stem Source: https://www.gene.com/stories/targeting-the-achilles-heel-of-influenza-viruses

Figure 4: The structure of HA, showing its head and more conserved stem
Source: https://www.gene.com/stories/targeting-the-achilles-heel-of-influenza-viruses

The regions of a virus to which antibodies can bind are known as epitopes. While the flu viruses are always prone to mutations, some epitopes remain conserved every season. These conserved regions are the keys to a broader and longer-lasting influenza vaccine. If a vaccine can recruit antibodies to these epitopes, those antibodies ideally should be able to prevent flu infections every year. Each of the eleven proteins found in the flu virus have been found to have conserved regions.

Accordingly, the potential for targeting each protein has been tested, and some promising results found. The M2 ion channel, for example, is a very conserved region that has shown potential in mice for reducing symptoms, though not so much potential in preventing illness [11]. Jacco Boon, an associate professor at Washington University School of Medicine was involved in a study that failed to show a cross-protective effect of targeting the M2 protein. “In order to prevent infection,” Boon commented, “you need to target the part of the virus that binds to your cells, and that is the hemagglutinin.” Indeed, the HA protein, specifically the stem portion (See Figure 4), contains the region that appears to have the most potential [12]. It is larger, more easily accessible, and invokes a stronger immune response than other proteins on the virus. In conventional flu vaccines, antibodies are trained to target epitopes mostly on the globular head of the HA protein. Accessing the stem is a challenge, partly because the large head shields it, partly because the head provokes a very strong immune response, and partly because the virus has evolved to protect its more conserved regions. The simplest solution is to carefully remove the head of the HA protein from the virus to use in the vaccine (See Figure 5). Ideally, this will prompt the body to create many antibodies that target the stem specifically. Through a trial on mice, it was found that targeting the entire HA protein does not provide cross-protection, but targeting the stem region does so with 70% success (See Figure 6). Similar tests on mice as well as ferrets have provided promising results for the headless HA target [13]. Boon also noted that “a lot of people are looking at the neuraminidase as a potential target” and that the elusive universal vaccine would likely recruit antibodies to the stems of both the HA and NA proteins.

Figure 5: The mechanism of removal of the HA protein’s head. Source: http://mbio.asm.org/content/1/1/e00018-10/F1.large.jpg

Figure 5: The mechanism of removal of the HA protein’s head. Source: http://mbio.asm.org/content/1/1/e00018-10/F1.large.jpg

Figure 6: Results from a lab test on groups of mice: Survival rates of those immunized with the headless-HA protein (white circles) are significantly greater than the two control groups, as well as headless HA-proteins that have undergone heat treatment. Source: Sagawa, H., Ohshima, A., Kato, I., Okuno, Y. & Isegawa, Y. The immunological activity of a deletion mutant of influenza virus haemagglutinin lacking the globular region. J. Gen. Virol.77, 1483–1487 (1996).

Figure 6: Results from a lab test on groups of mice: Survival rates of those immunized with the headless-HA protein (white circles) are significantly greater than the two control groups, as well as headless HA-proteins that have undergone heat treatment.
Source: Sagawa, H., Ohshima, A., Kato, I., Okuno, Y. & Isegawa, Y. The immunological activity of a deletion mutant of influenza virus haemagglutinin lacking the globular region. J. Gen. Virol.77, 1483–1487 (1996).

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Obstacles

According to Dr. Lawrence, it is very difficult to tell when a universal influenza vaccine will be created. While the progress in flu vaccine technology that has been made in the past decade is a good sign, challenges still remain in preparing a permanent solution for humans. One major issue is the HA protein stem, and its relatively poor ability of recruiting antibodies compared to the HA head. There are also concerns that a stronger flu vaccine could leave the human body more susceptible to other viral diseases [14]. Additional such risks will necessitate further testing and human trials.

Conclusion

Influenza, to this day, remains one of the greatest public health threats to humans every year. Through advances in computing technology, we have made progress over the last 10 years in understanding the virus and creating vaccines that are safer and more protective than before. However, the flu is as prevalent as ever, and it remains very difficult to predict which strain variants will circulate in the upcoming flu season. Conserved regions of the virus have shown promising potential for a future influenza vaccine that is as protective and long-lasting as a measles or polio vaccine. To develop a universal flu vaccine for humans will require further testing, and the timeline of an eventual perfect solution is unclear. Nevertheless, there is reason to be hopeful; with rapidly emerging technology, especially in genome sequencing, we may continue to utilize more resources than ever to propel us toward this goal. At the very least we should hope for an annual flu vaccine that is consistently effective, or a broader, but longer-lasting injection. Dr. Lawrence believes that we are likely to see one of these innovations in the near future. A permanent one-size-fits-all influenza vaccine may take longer, but it is the ultimate goal.

Edited by: Usama Ismail



Daniel Teich is a sophomore from Newton, MA. He can be reached at dteich@wustl.edu


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