The surge of universal influenza vaccines

Most of the current vaccines are made by one or a few antigens of the etiologic agent of the disease they are designed to prevent. In some cases, the whole set of antigens, either as an inactivated or as an attenuated viral or bacterial body is used. Historically, these highly focused vaccines proved to be an invaluable resource to combat dreadful epidemics, eliminate or control plaguing diseases, and even eradicate their etiological agent as in the case of smallpox. There is large consensus that properly used vaccines have been one of the greatest successes of modern medicine. The major problem now appears to be in expanding the practice of vaccination in vaccine non-compliant areas and broaden the vaccines spectrum to target many other highly incident and lethal, diseases [1,2].

As discussed elsewhere [2], we should nonetheless recognize that some of the current vaccines have limitations, and their benefits are challenged by several factors that, if dealt with complacently, could undermine people’s confidence in the vaccination as a safe and effective health measure. An incomplete list of the above factors is reported in Table 1.

Table 1.

Some factors affecting vaccine protection and influencing confidence in the health benefits of the current vaccines.^a

Increase in the number of recommended vaccines and their difficult insertion in the established, effective vaccination schedules

Difficulties in expanding pluricombined vaccines without altering the quality and the efficacy of single vaccines constituents or introducing stabilizing and preservants of real or perceived source of untoward side effects

The existence of multiple natural variants (serotypes, biotypes) with insurmountable difficulties in combining all of them into a single vaccine formulation

The positive selection exerted by the vaccine usage on bacterial and virus variant, leading to the replacement of the vaccine strain and circulation of vaccine-uncovered types

Antigenic drift and shift phenomena

^aadapted from Ref. [2].

Most challenging is the microbial ability to rapidly vary their antigenic asset and select for mutants poorly recognized by the immunized individuals, a process occurring naturally and / or enhanced by the selective pressure of vaccine usage. A special case in point is that of influenza vaccines which remain the stronghold in the fight against a virus which causes, annually, millions of cases of severe disease and 500,000 annual deaths [3]. Antigenic drift of its envelope glycoproteins, in particular its hemagglutinin (HA) constituent, calls for annual reformulation of the vaccine, a unique, costly and untoward aspect of the seasonal influenza vaccines. Less frequently but more threatening, major antigenic shifts lead to the emergence of a new virus with pandemic potential. In the last case, the time needed for vaccine production, testing, and approval by the regulatory bodies, despite the efforts recently made to shorten each of the above steps, can make the vaccine available after the epidemic peak, therefore with little impact on the pandemic control. This becomes particularly frustrating when the occurrence of a new pandemic virus had long been anticipated, as was the case for the 2009 H1N1 virus [4]. Therefore, the identification of virus protective antigens shared at hetero-subtypic level, thus ideally immunizing against both drifting and shifting antigenic virus variants, a so-called ‘universal’ vaccine, had long been considered as desirable as it was unachievable.

In the last few years, the dream of producing and clinically testing a universal influenza vaccine seems to be rapidly approaching reality, helped by the technological advancements of the last two decades. particularly concerning the identification of common, variant-shared protein sequences, and the use of viral vectors and ajuvants /carriers with a high capacity of stimulating effective antigen presentation and processing. Attention has been particularly focussed upon highly conserved sequences of the HA stalk and M2 protein, together with other internal antigens (Figure 1). In a paper published in the inaugural issue of the Journal mBio, Steel, Palese and collaborators first showed that a vaccine based on a conserved region of the viral HA stalk induced cross-protective, virus neutralizing antibodies, and was protective against a challenge in mice [5]. More recently, work by the same research group has shown that optimal protection against influenza virus challenge in animal recipients of the above ‘stalk vaccine’ required the induction of broadly neutralizing antibodies efficiently binding the Fc receptor on cells of innate immunity, including neutrophils, in a previously unsuspected role of these eminently phagocytic cells for anti-influenza protection [6]. Broadly protective antibodies have also been raised by immunization with a cocktail of virus-like particles expressing such distinct HA proteins as the H1, H3, H5, and H7 ones. Importantly, vaccinated mice could resist challenge by both intra- and hetero-subtype virus variants [7]. It would be of interest to compare immune mechanisms elicited by the VLP vaccine with the complex one elicited by the stalk vaccine. Other approaches to universality are ongoing [8].

Figure 1.

A simplified scheme of the influenza A virion particle with indication of the segmented RNA genome and pericapsidic membrane antigens, including those more commonly used as components of universal influenza vaccines.

Overall, universal influenza vaccines continue to surge. In this issue of Pathogens and Global Health, two different efforts aimed at confirming and expanding on this important research field are provided by Castrucci and Donatelli’s research group at ISS, Rome, together with Siccardi and collaborators at HSR, Milan, Italy. They describe the production of a modified vaccinia virus Ankara (MVA) which expresses the HA stalk domain of the pandemic 2009 H1N1 influenza virus. In mice, this construct was able to induce broadly cross-reactive antibodies and cell-mediated immune responses but not neutralizing antibodies, and was unable to confer protection from the virus challenge. Misfolded conformation and instability of the antigen have been advocated as possible causes of vaccine failure to induce protective antibodies against conformational epitopes. Whether other functional antibodies binding the Fc receptor on innate immune cells were induced by the MVA-vectored antigen was not investigated [9]. In the accompanying paper [10], these research groups report other data showing that MVA-vectored internal antigens of the virus, including Nucleoprotein Polymerase PB1 and M1 (Figure 1) were indeed highly efficient T cell immunogens in a HLA-A2 transgenic mouse and could generate protective anti-influenza immunity. The protection was associated with induction of antigen-specific CD8+T cell-mediated immunity. Although no proof was provided that protection was really contributed to by these CD8+T cells, their possible involvement in vaccine-induced immunity appears to be of interest and provides some further evidence that universal influenza vaccines, depending on their composition, can use different protective patterns of immune responses.

As suggested for the universal stalk vaccine [6], and also for internal antigens-based vaccines, immune responses adding to the neutralizing antibodies may be required for optimal protection. Despite their limitations, the above studies significantly expand the validity of MVA vectors for inducing high-level immunity and invite us to consider more than one conserved viral epitopes as a possible multicomponent vaccine. Overall, they confirm the difficulties but also the basic feasibility of distinct universal influenza vaccines. With a touch of optimism, the present state-of-the-art universal influenza vaccines promise more reality than dream.