Escaping a universal flu vaccine

It’s my job to think about how to best make use of antibodies in the protection against pathogens. Part of this is identifying where a problem may exist for antibodies to clear the infection. My previous blogposts about Malaria and HIV touched on this concept, but my favourite example is the subject of today’s blog: Influenza. 

Flu infections are truly part of life. We all know about them, we all get them. Even with my collective knowledge on how the immune response could best dispose of influenza, I am not immune to it. I am, however, able to get rid of it once I get it. But some are not so lucky. In the US in the past year: 

·       >50 million people were infected with the flu

·       >26 million people visited a physician for flu infection

·       >700,000 were hospitalised for flu

·       >40,000 people died from flu

Flu can be particularly deadly to the very young, the very old, and the immunocompromised. We continue to live with it, each ‘flu season’, primarily due to the concept of ‘antigenic drift’. This refers to the ability of influenza to rapidly mutate, rendering pre-existing immunity against the virus largely ineffective. This viral escape strategy under the pressure of our immune system is not unique to influenza, but the flu is a particularly elegant example of viral persistence in the community. 
Throughout history, we have seen the flu become devastating variants of itself. For example, the 1918 Spanish Flu pandemic killed between 50-100 million people world-wide. 

The combined economic and healthcare burdens driven by influenza infection have warranted substantial global efforts to generate a ‘universal vaccine’ that is capable of protecting against any future influenza virus regardless of its mutational capacity. 

The widespread support for this possibility is underpinned mostly by our understanding of how the structure of the virus mutates over time. Our immune response directs most of its efforts against a region of the virus called the hemagglutinin (HA) head (see blueprint diagram). Consequently, this region generates many ‘escape’ mutants of the virus that allows it to evade immunity. The ‘stem’ of HA is more conserved between influenza viruses, primarily for two reasons: first, the immune response is not good at targeting it, as the head region attracts most of the attention and resources (we call this immunodominance). Second, the stem is constrained by structural requirements for the virus, meaning that mutations in the stem region can often lead to useless influenza viruses that are not fit for infecting a host. Therefore, the virus tries not to mess too much with that region and has minimal immune-related reasons to do so. This makes it a great vaccine target.

While I am optimistic and excited about the prospect of a universal flu vaccine against the stem as a ‘conserved’ target, I have never been convinced that influenza would not simply mutate this region, too. Scientists at the National Institutes of Health in the US also appear to be sceptical. They directly tested whether the virus could evade neutralizing antibodies against the stem through a series of experiments published in the leading journal Nature Medicine that I will summarise below.

The authors first note a spontaneous mutation in the stem region generated a version of the virus that behaved almost indistinguishably from the native virus. The mutation did not affect the replicative fitness or clinical disease associated with infection. This underscores the possibility of a naturally-occurring mutant virus that deviates from the ‘conserved’ stem structure without compromising its infectivity. 

They then showed that a series of well-known neutralizing antibodies against the native stem were less capable of binding the mutant stem and provided a structural basis for this inefficiency. The virus could also resist pre-existing antibodies targeting the stem region in humans. Hosts with high levels of stem-specific antibodies more frequently selected for the expansion of the mutant virus over the native virus. This indicated not only that infection with the mutant would be poorly controlled by a vaccine which elicited immunity against the native stem, but that it would be driven to succeed in the host, reinforcing its escape. 

Their collective data questions the potential of universal flu vaccine strategies against stem epitopes, candidates for which are currently being evaluated in clinical trials. However, all is not lost in our hopes to address this problem. The knowledge of escape mutant capacity is important – it allows us to refine our vaccine strategies against a broader array of targets based on possible mutants. Indeed, the utility of some antibodies that recognise the stem was not affected by the mutation, highlighting the possibility that these antibodies are our best efforts for broad neutralization of escape mutants. 

I remain confident in a vaccine for the flu, and you should too. 

By Jeremy Brooks

Link to the primary article here

Adapted from Frontiers in Science