Emerging influenza viruses and the prospect of a universal influenza virus vaccine.

Biotechnology Journal

Biotechnol. J. 2015, 10, 690–701

DOI 10.1002/biot.201400393

www.biotechnology-journal.com

Review

Emerging influenza viruses and the prospect of a universal influenza virus vaccine Florian Krammer Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Influenza viruses cause annual seasonal epidemics and pandemics at irregular intervals. Several cases of human infections with avian and swine influenza viruses have been detected recently, warranting enhanced surveillance and the development of more effective countermeasures to address the pandemic potential of these viruses. The most effective countermeasure against influenza virus infection is the use of prophylactic vaccines. However, vaccines that are currently in use for seasonal influenza viruses have to be re-formulated and re-administered in a cumbersome process every year due to the antigenic drift of the virus. Furthermore, current seasonal vaccines are ineffective against novel pandemic strains. This paper reviews zoonotic influenza viruses with pandemic potential and technological advances towards better vaccines that induce broad and long lasting protection from influenza virus infection. Recent efforts have focused on the development of broadly protective/universal influenza virus vaccines that can provide immunity against drifted seasonal influenza virus strains but also against potential pandemic viruses.

Received 26 AUG 2014 Revised 06 JAN 2015 Accepted 03 FEB 2015

Keywords: Avian influenza · Heterosubtypic immunity · Pandemic influenza · Universal influenza virus vaccine · Zoonotic influenza

1 Introduction Influenza viruses are a major public health problem and cause significant morbidity and mortality worldwide. Influenza epidemics occur during the winter seasons of the Northern and Southern Hemisphere and claim up to 500 000 lives annually. Licensed vaccines against seasonal influenza viruses are highly effective and are so far the best countermeasure against influenza virus infection. However, they induce a very narrow, strain-specific immune response against the immunodominant globular

Correspondence: Dr. Florian Krammer, Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1124, New York, NY 10029, USA E-mail: [email protected] Abbreviations: ADCC, antibody dependent cell mediated cytotoxicity; CDC, complement dependent cytotoxicity; cHA, chimeric hemagglutinin; COBRA, computationally optimized broadly reactive antigen; DNA, deoxyribonucleic acid; HA, hemagglutinin; HI, hemagglutination inhibition; LAH, long alpha helix; M1, matrix protein 1; M2e, matrix protein 2 ectodomain; MVA, modified vaccinia Ankara; NA, neuraminidase; NP, nucleoprotein; VLP, virus-like particle

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head domain of the hemagglutinin (HA), the major surface glycoprotein of the virus and do not protect against antigenically drifted strains [1]. Therefore, these vaccines have to be updated and re-administered on an annual basis – a laborious, time consuming and costly undertaking. In addition, strain updates rely on predictions of future circulating strains using surveillance data, and such predictions are not always accurate. If the selected vaccine strains do not match the circulating strains, vaccine efficacy drops sharply [2, 3]. Based on recent data this problem might also affect the 2014/15 seasonal influenza virus vaccine since a large proportion of the circulating H3N2 belongs to a drift variant that does not match the H3N2 vaccine strain [4]. In addition to seasonal epidemics influenza viruses also cause pandemics at irregular intervals. Pandemics are usually initiated by viruses that spill over from the animal reservoir, break the species barrier and become efficient in replicating and transmitting in humans. This process usually includes re-assortment of zoonotic viruses with circulating human influenza virus strains resulting in viruses that have surface antigens to which humans are naive and internal proteins that are well adapted to the human host. Influenza virus pandemics

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Figure 1. Dynamics of influenza virus strains circulating in humans and phylogenetic tree of HA and NA subtypes. (A) shows the dynamics of influenza viruses in the human population during the last 100 years. The changing color of the bars represents antigenic drift. (B) Phylogenetic tree of influenza A and B HAs. Group 1 and Group 2 HAs are indicated. (B) Phylogenetic trees of the influenza A and B NAs. Group 1 and Group 2 NAs are indicated. (A), (B) Subtypes that have shown their ability to sustain circulation in humans are marked with red stars. Subtypes that occasionally infect humans are marked by blue stars. Scale bars represent a 7% change on the amino acid level. Trees were build using ClustalW and were visualized in FigTree.

occurred in 1918 (H1N1), 1957 (H2N2), 1968 (H3N2) and most recently in 2009 (H1N1) (Fig. 1). Unfortunately it takes relatively long (about 6 months) to produce and distribute vaccines against a novel pandemic influenza virus and often – like in 2009 – vaccines are delivered only after the first wave of the pandemic already hit the population (http://www.virology.ws/2010/12/09/pandemic-influenza-vaccine-was-too-late-in-2009/).

2 Emerging influenza viruses in Asia and Europe: Avian-swine H1N1, H5N1, H5N5, H5N6, H5N8, H6N1, H7N9, H10N7 and H10N8 With at least two pandemics (H2N2 and H3N2) and many potential pandemic viruses originating in Southeast Asia, this geographic region seems to be a hotspot for emerging influenza viruses. The high human population density in combination with a high density of avian and swine livestock – very often in close proximity to humans – create an extensive interface for cross-species transmission. Highly pathogenic H5N1 viruses first appeared in Hong Kong in 1997 [5] (Table 1). These viruses remain incapable of human-to-human transmission but possess a multibasic cleavage site in their HA which allows for systemic virus replication in avian species and causes high case fatality rates in humans. However, overall mortality rates


are probably low since a relatively high percentage of the rural population seems to be seropositive for these viruses most likely due to exposure and subclinical infection [6–8]. Nevertheless, highly pathogenic H5N1 viruses are now prevalent in avian populations in Asia, Europe and Africa and are considered a potential pandemic threat. In addition to H5N1 a fatal case of H5N6 was reported in early 2014 in the Chinese province of Sichuan (http:// www.cnn.com/2014/05/07/health/h5n6-flu-china-death/), a second human infection with this virus was reported in December 2014 in Guangdong (http://www.china.org.cn/ china/Off_the_Wire/2014-12/23/content_34393283.htm) and a third cases (fatal) occurred early in 2015 in the Diqing Tibetan Autonomous Prefecture, Yunnan Province, China (http://www.who.int/csr/don/12-february-2015avian-influenza/en/). Furthermore, a novel clade of highly pathogenic H5 viruses (clade 2.3.4.6) has recently spread in wild birds and domestic poultry in Korea, China and Japan [9–16]. This new H5 HA mostly occurs as H5N8 virus but seems to be relatively promiscuous in its NA choice and was also found as re-assortant with N2 and N5 NA [9]. In 2014 – after migrating to Europe – this virus has caused immense problems infecting poultry in Germany, the Netherlands, Italy and the United Kingdom (http://www.recombinomics.com/News/12271401/H5N8_ Fujian_Japan_3_Sub.html) [12]. In late 2014 a related virus (as H5N8 and H5N2 subtypes) was also detected North America causing disease in poultry, a captive fal-

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Table 1. Recent human infections with zoonotic influenza viruses

Virus subtype

Year

Avianswine H1N1

Country/ Region

Human cases

Origin

Comments

References

China

2 reported plus serological evidence in swine farm residents

Swine

Antigenically relatedness to pH1N1 and pre-pandemic seasonal H1N1

[31, 138, 139]

H5N1

1997, 2003 – to date

Eurasia and Africa

694 confirmed cases, 402 deaths (as of January 6th, 2015)

Avian

The high case fatality rate might not be reflecting the fatality rate since seroprevalence seems to be relatively high in humans in Southeast Asia

[6] http://www.who.int/ influenza/human_animal_ interface/HAI_Risk_ Assessment/en/

H5N6

2014

China

3; acute severe pneumonia; 2 fatal

Avian

Unclear if multibasic cleavage site was present

http://www.cnn.com/2014/ 05/07/health/h5n6-flu-chinadeath/, http://www.china.org. cn/china/Off_the_Wire/201412/23/content_34393283.htm

H6N1

2013

Taiwan

1; lower respiratory tract infection, non-fatal

Avian

H7N3

2012

Mexico

2, conjunctivitis

Avian

High path H7N3, outbreak in poultry might still be ongoing

[43, 140]

H7N9

2013 – to date

China

568 cases, 204 fatalities, mild to severe infections (as of February 8th, 2015)

Avian

Some family clusters occurred, unusual age distribution (more cases in the elderly)

http://www.who.int/ influenza/human_animal_ interface/influenza_h7n9/ Risk_Assessment/en/

H10N7

2010

Australia

2–7; conjunctivitis and minor upper respiratory tract symptoms

Avian

Slaughterhouse workers, exposure to infected chicken

[141]

H10N8

2014

China, Hong Kong SAR

3 (2 fatal); severe pneumonia

Avian

con and in wild birds (http://www.recombinomics.com/ News/12271401/H5N8_Fujian_Japan_3_Sub.html). Low pathogenic avian influenza viruses – most prominently H7N9 – have recently also caused significant numbers of human cases in China. H7N9 was first detected in early spring 2013 in China’s Anhui province and in Shanghai [17] (Table 1). Although case numbers dropped during the summer months, the virus caused a second wave of infections during the winter season of 2013/14 with a case fatality rate of approximately 30% (http://www.who.int/ influenza/human_animal_interface/influenza_h7n9/en/). In contrast to highly pathogenic H5N1 viruses, which

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[21]

[26, 27] http://www.wpro.who.int/ china/mediacentre/ factsheets/h10n8/en/; http://www.who.int/entity/ influenza/human_animal_ interface/Influenza_ Summary_IRA_HA_interface_ 25Feburary14.pdf?ua=1

cause significant morbidity and mortality in birds, this virus shows low pathogenicity in avian species and spreads almost undetectably in livestock and wild birds [18]. It is to be expected that the virus will maintain its seasonal pattern and it is likely that case numbers will rise again in the winter season 2014/15. Although no sustained human-to-human transmission has been reported for this virus, its increased presence in the human host augments the chance of this strain to re-assort with seasonal human influenza viruses and gain mutations that allow it to transmit efficiently in humans, and it therefore represents a potential [19] pandemic threat. Another low



Biotechnol. J. 2015, 10, 690–701


pathogenic virus that has recently been detected for the first time in humans in Taiwan is of the H6N1 subtype [20–22] (Table 1). Subsequent analysis of H6 strains (with multiple neuraminidase (NA) subtypes) circulating in China has revealed that many of these viruses are able to bind to human-like receptors and to transmit by direct contact in the guinea pig model [23]. In China, H6 viruses have also been isolated from pigs, which are seen as mixing vessels for avian and human influenza viruses [24]. Furthermore, experimental inoculation has shown that H6 viruses are able to replicate and cause disease in man [25]. In addition to H6N1 viruses, three human H10N8 cases were reported in China early in 2014, two of them fatal [26, 27] (Table 1). A similar virus, H10N7, caused an extensive outbreak among seals on the coasts of Germany, Denmark and Sweden in 2014 [28]. However, our knowledge about the prevalence of these viruses in wild avian species and livestock as well as their pathogenicity and transmissibility in mammals is limited [29, 30]. With the current lack of information about H10 viruses, it is not possible to assess the pandemic potential of this subtype. Finally, antibodies against Eurasian avian-swine lineage H1N1 viruses have recently been detected in Chinese farmers [31] (Table 1). H1 HAs of this lineage are distantly related to the H1 HAs of the 2009 pandemic H1N1 HA (classical swine lineage) and the pre-pandemic seasonal H1N1 HA (human lineage). H1N1 has shown its capability to start a pandemic twice and the Eurasian avian swine H1 is divergent enough to evade immunity raised against the pandemic 2009 H1N1 strain and the pre-pandemic seasonal H1N1 strains [32]. Furthermore, the 2009 pandemic H1N1 virus was able to establish itself in the pig population in Southeast Asia [33] and could contribute its key human transmission factors – like its M segment [34, 35] – to novel re-assortants. Although the pandemic potential of these viruses is in general low it is crucial to intensify surveillance and develop appropriate countermeasures that could be used in the case of a pandemic.

3 Pigs, seals, chickens and bats: Pandemic influenza virus threats from the Americas? The most recent pandemic – H1N1 in 2009 – had its origin most likely in the North American pig population. In addition, several other influenza viruses of concern have been detected in the Americas. In 2006, an H2N3 virus was isolated from pigs in the USA [36]. H2 viruses have caused a pandemic in 1957 but vanished from the human population in 1968 [37]. Therefore, immunity against H2 viruses is likely low in humans, specifically in the generations born after 1968 [38]. Similarly, an H3N2 variant virus emerged in the US swine population that started to cause human cases – contracted mostly at agricultural fairs – in 2011 [39, 40]. Another North American avian H3 strain (H3N8) has raised concerns when it infected harbor seals



in Massachusetts with a high mortality rate [41]. H3 variant viruses are of specific concern since this subtype has already proven that it can cause high morbidity and sustain transmission in humans. Similar to the Eurasian avian-swine H1 HA, these H3 HAs are sufficiently different from currently circulating H3N2 viruses and younger generations, specifically, might not have neutralizing antibody responses against these strains [42]. In addition to mammalian virus isolates of concern, North America has seen several outbreaks of highly pathogenic H7 viruses in poultry, the latest being H7N3 in the state of Jalisco in Mexico in 2012. In this case several poultry workers contracted the virus and developed conjunctivitis [43]. Finally, novel influenza viruses (H17N10 and H18N11) have been detected in Peru and Guatemala [44, 45]. However, it is unclear if the surface glycoproteins of these viruses support replication in human cells and re-assortant experiments have shown that the internal genes of H17N10 are incompatible with internal genes of other avian and mammalian influenza A viruses [46]. The pandemic potential of these novel viruses, therefore, is likely low.

4 New technologies that allow a fast response to pandemic influenza virus threats As described above, several influenza viruses with pandemic potential can be found in the avian and mammalian reservoir. However, a new pandemic could also be caused by an unexpected virus as it happened with H1N1 in 2009. Surveillance efforts have improved since then and have increased the likelihood of detecting a potentially dangerous virus in the animal reservoir but worldwide coverage of all host species is not possible. Manufacturing influenza virus vaccines for a novel pandemic strain in time remains a challenge as demonstrated during the 2009 pandemic when the first batches of vaccines were distributed well after the first pandemic wave hit the population in the USA (http://www.virology.ws/2010/12/ 09/pandemic-influenza-vaccine-was-too-late-in-2009/). A number of technologies have been advanced and developed since then, which could speed up vaccine manufacturing (Table 2). The use of cell substrates instead of embryonated eggs allows for relatively easy scale-up of the production process [47–51]. In addition many virus isolates can be grown in cell culture without the need to make high growth re-assortant viruses – which is a time consuming process [52]. The implementation of gene synthesis and reverse genetics technologies into these processes now allows for the rapid creation of genetically modified viruses from sequence information alone [49, 53, 54], and seed viruses can be generated without the need to physically ship viral samples. Furthermore, the first recombinant HA-based vaccine was licensed in the USA

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Table 2. Advances to improve seasonal and pre-pandemic influenza virus vaccines

Technology

Effect

Comments

Novel adjuvants

Better and longer lasting immune response

Some safety concerns

Cell culture

Wild type viruses can be used, up-scaling is easier than with egg-based production

Limited capacity worldwide, questionable economic viability

Reverse genetics

Modified viruses can be rescued de novo from a DNA template, excludes possible contaminations from wild type viruses, makes re-assortment easier

Gene synthesis

Any virus sequence can be made de novo from sequence data only and can then be rescued via reverse genetics, viruses can be easily modified

Recombinant vaccines

Fast vaccine production, almost unlimited up-scaling, divergent range of expression systems, vaccines can be derived from sequences from patients without the need of egg/cell culture isolation of the virus which reduces the risk of antigenic variations due to substrate adaption

Quadrivalent vaccines

Reduce the impact of influenza B virus vaccine strain mismatches

Heterologous prime-boost regimens

Induction of broader and longer lasting vaccine responses, can be used to prime the population for a heterologous pandemic vaccine that is given in the future

in 2013 (http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm335891.htm). Using this technology – which is based on expression in insect cells via the baculovirus system – allows to produce vaccine without the need to handle live virus [55]. This also circumvents possible antigenic changes that viruses can acquire during adaption to the isolation/production substrate (e.g. cells or embryonated eggs) [56]. A panel of other novel production methods that allow rapid production of pandemic vaccines (such as insect cell [55, 57–59], plant [60, 61] and bacterial systems [62, 63]) are currently in late stage clinical development. In addition, novel adjuvants have been licensed for the use with pandemic vaccines [64]. These adjuvants allow for dose sparing and help to reduce the number of vaccine doses that are required to induce protective immunity. This is especially important for vaccines based on avian viruses since they are usually not very immunogenic in humans if the traditional correlate of protection (the hemagglutination inhibition titer [65]) is used to assess their efficacy. Another recent development includes heterologous prime-boost regimens that induce longer and broader immune responses than classical vaccination [66–68]. These technological advances are able to speed up vaccine production considerably but a lot of time is still lost for necessary processes like strain selection, reagent development and efficacy trials and it is therefore hard to estimate a realistic response time in case of a new influenza pandemic.

694

Vaccine quality depends on the expression system and purification technology, plant and bacteria-based approaches might be more suitable for low-resource countries

Heterologous prime-boost regimens usually include an LAIV or DNA prime followed by a viral-vector, protein or inactivated virus vaccine

5 Heterosubtypic immunity: A long term sustainable solution against influenza virus infections? Immune responses against the influenza virus tend to be narrow and strain specific. However, using specific vaccine constructs (as described below) the immune response can be redirected to conserved epitopes that are shared between divergent influenza viruses. This crossprotection can be classified as heterologous protection (within one subtype, e.g. H1) or as heterosubtypic protection (including multiple subtypes). Neutralizing antibody responses induced by seasonal inactivated influenza virus vaccines tend to be focused towards the membrane distal immunodominant globular head domain of the viral HA [69]. This part of the HA has a high plasticity and is mostly responsible for the antigenic drift of influenza viruses [70]. Viruses are therefore able to escape the immune response and influenza virus vaccines have to be re-formulated and re-administered every year [71]. The membrane proximal stalk domain of the HA is – in contrast to the head domain – relatively conserved, likely due to functional and structural constraints. Antibodies against this domain are rare due to its immunosubdominant nature but have been isolated from mice and humans in recent years [72–80]. Due to the conservation of the stalk domain these antibodies are crossreactive even between different subtypes of influenza HAs. They are able to neu-



Biotechnol. J. 2015, 10, 690–701


tralize the virus through a number of mechanisms including inhibition of fusion of the viral and endosomal membrane, inhibition of viral egress and inhibition of HA maturation [74–79, 81]. In addition they have been shown to work through antibody dependent cell mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) [82, 83]. These stalk-reactive antibodies have been successfully tested as therapeutics and prophylactics against influenza virus infections in mice and ferrets and might be valuable for human treatment as well [84, 85]. However, monoclonal antibody prophylaxis or therapy is costly and complicated to administer on a population wide basis. A vaccine that induces high titers of this type of antibody would therefore be preferable. Another conserved target on the virus surface is the ectodomain of the M2 ion channel, termed M2e. This 24-amino acid ectodomain can be targeted by antibody responses that mainly protect through ADCC but are non-neutralizing [86–88]. In addition to antibody responses, T cells have been shown to be able to provide heterosubtypic protection against influenza virus infection [89]. Strong T-cell responses are induced by internal influenza virus proteins like the nucleoprotein (NP) and the matrix protein (M1) [89]. These proteins are highly conserved as compared to the surface glycoproteins and might therefore be a valuable vaccine target as well. Vaccine strategies that are based on heterosubtypic immunity might be able to replace the seasonal influenza virus vaccines (which need to be updated annually) due to the conserved nature of their targets, but would also provide protection from emerging pandemic viruses [90]. Therefore the development of this kind of vaccine might be a long-term sustainable solution for the fight against influenza virus infections.

6 Searching for the Holy Grail: A truly universal influenza virus vaccine A number of universal influenza virus vaccine candidates – mostly based on the targets described above – are currently in late stage pre-clinical or in early stage clinical development [90] (Table 3). A strategy based on the use of chimeric HA (cHAs) has been proposed by our groups at Icahn School of Medicine at Mount Sinai. Chimeric HAs are combinations of H1 (group 1) or H3 (group 2) stalks with exotic globular head domains, mostly of avian origin [91]. These constructs are functional, fold similar to wild type HA and influenza viruses expressing these constructs can be rescued and grown to high titers [91]. Sequential exposure to cHAs that possess the same stalk domain but divergent head domains specifically induces stalk reactive antibodies [70]. Since the same stalk domain is presented to the immune system repeatedly the stalk response is boosted while the divergent globular head domains – which are immunodominant under normal circumstances -– only induce a primary immune



response. This vaccine candidate shows efficacy against divergent viruses including H5N1, H6N1, H7N9 and H10N7 in the mouse and/or ferret model [70, 84, 92, 93]. In addition it has recently been shown that exposure of humans to HAs with divergent head but conserved stalk domains also induces stalk-reactive antibodies [94–99]. This recent data provides evidence that a cHA-based universal vaccine strategy might also be feasible in humans. Chimeric HA-based vaccines can be produced using a variety of platforms including inactivated whole, split or subunit vaccines, live attenuated vaccines, recombinant protein vaccines, virus-like particles, virus vectored vaccines, DNA vaccines and others. Clinical trials with cHA vaccine candidates will reveal the full potential of this approach in the near future. Another approach to induce high levels of stalk-reactive antibodies is based on the complete removal of the immunodominant globular head domain. These headless HA constructs are usually immunogenic and induce limited protection in animal models [100–105]. However, removal of the globular head domain impacts on the folding of the stalk domain and many stalk-reactive antibodies – which almost exclusively bind to conformational epitopes – do not recognize these constructs very well. Headless HA immunogens that show better stability and folding would be needed to advance this approach further. Since headless HA would not support replication of influenza viruses due to the lack of a receptor binding domain possible platforms for a headless HA vaccine are recombinant protein, virus-like particles, DNA vaccines, viral vectors and others. A regulatory issue with stalk-based vaccine approaches is that stalk-reactive antibodies do not induce hemagglutinination inhibition (HI) active antibodies. HI titers of >1:40 are an established correlate of protection for seasonal influenza virus vaccines and new vaccines are licensed on the basis of HI induction as surrogate for efficacy in preventing infection. For vaccines that do not induce this kind of immunity efficacy has to be shown directly by prevention of virus infection, which requires vaccine trials with large numbers of participants. However, stalk-based vaccines do induce neutralizing antibodies and assays based on in vitro neutralization can be further developed as correlate of protection. Another HA-based approach that is far in pre-clinical development is the computationally optimized broadly reactive antigen (COBRA) approach [106, 107]. This method uses a merged sequenced based on many divergent HA sequences from one subtype to induce HI active antibodies to the globular head domain [106]. COBRA HAs have been very successful for the development of broadly protective H5 vaccines and are now developed for other influenza A and B viruses as well [108–110]. However, immunity induced by COBRA HAs might be limited to one subtype or specific clades within one subtype making them less cross-protective than the anti-stalk

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Table 3. Broadly protective/universal vaccine approaches

Technology

Mechanism of action

Platform

Development stage

Breadth

Developer

Chimeric HAs

B-cell/antibody mediated

Inactivated influenza virus vaccine, live-attenuated influenza virus vaccine, recombinant, DNA, viral vector or virus-like particle

Late pre-clinical

HA group-specific, trivalent vaccine might cover all influenza A and B strains

Icahn School of Medicine at Mount Sinai

COBRA HAs


Inactivated influenza virus vaccine, live-attenuated influenza virus vaccine, recombinant, DNA, viral vector or virus-like particle

Late pre-clinical

Subtype/clade-specific, polyvalent vaccines might cover all human influenza viruses

Vaccine and Gene Therapy Institute (VGTI) Florida

Headless HA


Recombinant, DNA, viral vector or virus-like particle

Early pre-clinical

HA group-specific, trivalent vaccine might cover all influenza A and B strains

Icahn School of Medicine at Mount Sinai, Stanford University, Merck, Indian Institute of Science

M2e

Mostly antibody mediated

Recombinant, DNA, viral vector or virus-like particle

Clinical

Might cover all influenza A strains

Multiple

MVA expressing M1-NP

T-cell mediated

Viral Vector

Clinical

Might cover all influenza A strains

The Jenner Institute, University of Oxford

Multimeric-001

Complex

Recombinant

Clinical

A and B strains

BiondVax

approaches. An advantage is that these constructs induce HI responses, which facilitates approval by regulatory agencies. Similar to the cHA approach, the COBRA concept is platform independent and live virus expressing these constructs can be rescued. One of the first universal influenza virus vaccine targets was the ectodomain of the M2 ion channel of the influenza virus, M2e [86, 88]. The M2 protein is present on the virus only in small copy numbers and binding of antibodies to the viral M2 does not neutralize the virus. However, the protein is expressed in larger quantities on the cell surface and these cells are cleared by ADCC, which is probably the main mechanism of protection of M2e based vaccines [87, 88]. Many constructs including VLPs displaying M2e [88], flagellin-M2e [111], fusion constructs and multimeric/tetrameric M2e [112] have been successfully tested. However, due to the specific mechanism of protection it is hard to establish a correlate of protection and the vaccine usually does permit limited virus replication. M2e vaccines can be produced in a variety of systems and platforms including expression in mammalian and insect cells, yeast and also bacteria. In contrast to HA- and M2e-based vaccines which aim to induce humoral immune responses a recent viral vectored approach specifically focuses on the induction of a

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T-cell response [113, 114]. This vaccine candidate is based on a modified vaccinia Ankara (MVA) strain that expresses a fusion peptide of M1 and NP in the vaccinee. So far the vaccine was able to induce strong T-cell responses in humans [113, 114]. Although T-cell responses are probably an important component of the protection against influenza virus it is unlikely that a T-cell response by itself would be able to prevent an upper respiratory tract infection. A combination of the MVA vectored vaccine with seasonal inactivated influenza virus vaccine might therefore be a good strategy to induce broader immune responses against seasonal influenza viruses in combination with protection against mortality for shifted pandemic strains [115]. This vaccine approach is currently also tested using other viral vectors like adenovirus [116]. Finally, there are several epitope- or peptide-based universal vaccine approaches including the HA long alpha helix (LAH) [117], fusion peptide [118, 119] and virus-like particles that present stalk-epitopes [120, 121] tested in pre-clinical studies. An approach based on linear epitopes from HA, M1 and NP produced in bacteria is currently being tested in clinical trials [122]. Each of these vaccine approaches would enhance the immunological pressure against conserved target sites and it is therefore possible that these conserved domains





would become subject to antigenic drift. However, the plasticity of these conserved sites might be intrinsically restricted. As an example the stalk domain of HA needs to undergo complex conformational re-arrangements during the fusion process in the endosome and mutations in this region might impair the protein’s functionality. Escape variants with mutations in conserved epitopes might therefore show impaired fitness which might conceivably limit their spread in the population if they occur. Another important issue that needs to be taken into consideration for universal influenza virus vaccine design is the duration of the immune response. Influenza virus vaccines typically induce short-lived protective immune responses but an effective universal influenza virus vaccine would need to provide long lasting immunity to be of value. Several approaches using adjuvants and/or heterologous prime-boost vaccination regimens are currently developed to overcome this limitation.

7 A role for the viral neuraminidase as an influenza virus vaccine antigen?

Florian Krammer received his degree in biotechnology from the University of Natural Resources and Life Sciences, Vienna where he worked on insect cellderived influenza virus-like particles in the laboratory of Dr. Reingard Grabherr. For his postdoctoral work he joined Dr. Peter Palese’s group at the Icahn School of Medicine at Mount Sinai, New York where he focused on the development of a universal influenza virus vaccine. In 2014 Dr. Krammer became Assistant Professor (tenure track) at Mount Sinai. The Krammer laboratory studies on cross-reactive antibody responses against the surface glycoproteins of RNA viruses including influenza, hanta and filoviruses.

might be more immunogenic as well since this type of vaccine might break the immunodominance of the HA globular head domain [1].

8 Conclusions and outlook Neuraminidase (NA), the second influenza virus surface glycoprotein is largely ignored by vaccine manufacturers and regulatory agencies. The NA content of influenza virus vaccines is usually not measured or standardized and in many cases immune responses against the NA are not measured either. Furthermore, little is known about the anti-NA immunity present in the human population or the immune response that regular influenza virus vaccines induce [123]. In general it is thought that NA is immunosubdominant when given in a vaccine combined with HA as it is the case for regular inactivated influenza virus vaccines [124, 125]. Several studies in the 1970s, 80s and 90s indicated that this protein has untapped potential as a protective and even cross-protective vaccine antigen [126–128]. These studies showed that NA given without associated HA or with an HA subtype to which humans are naive is able to induce reasonable immune responses [125, 128–130]. Recently NA has gained increased interest as vaccine antigen again and tools to measure NA antigen content and the vaccine induced immune response to NA are being developed [131–134]. Although a conserved B-cell epitope has been described for influenza A and B NAs [133, 134] it is thought that cross-reactivity to NAs of different subtypes is rare. Cross-reactivity within subtypes seems to be relatively high and several groups recently reported NA-based cross-protection between pandemic H1N1 and H5N1 [135–137]. Vaccines that induce broad cross-reactivity within a subtype (e.g. N1) might be able to protect against mortality caused by divergent viruses that express N1 NAs like H1N1, H5N1 and H6N1. NA vaccines could be developed in addition to regular vaccines. Furthermore, NA presented in the context of a cHA-based vaccine


Several influenza virus subtypes including H3N2v, H5N1, H5N6, H6N1, H7N9 and H10N8 have recently caused disease in humans. These outbreaks are limited in case numbers and geographic distribution and their detection might be the result of enhanced surveillance and diagnostic techniques. However, influenza virus strains are causing pandemics in irregular intervals and therefore it is necessary to investigate the pandemic potential of these viruses and develop effective countermeasures against possible pandemics. Vaccination has so far resulted in the most efficient protection against influenza virus infection but producing a vaccine in response to a novel pandemic strain takes months. Several promising broadly reactive/universal vaccine candidates that induce heterosubtypic immunity in animal models are currently in late stage pre-clinical/early stage clinical development. A successful universal influenza virus vaccine could abolish the need for annual re-formulation and re-vaccination of the seasonal vaccine and also significantly improve our pandemic preparedness.

Florian Krammer was supported by an Erwin Schrödinger fellowship (J3232) from the Austrian Science Fund (FWF). Work in the Krammer laboratory is supported by PATH and the NIAID Centers of Excellence for Influenza Research and Surveillance (CEIRS) (HHSN266200700010C). The Krammer laboratory also receives funding from Glaxo SmithKline. Icahn School of Medicine at Mount Sinai has filed several patents regarding influenza virus vaccine constructs.

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ISSN 1860-6768 · BJIOAM 10 (5) 655–820 (2015) · Vol. 10 · May 2015

Systems & Synthetic Biology · Nanobiotech · Medicine

5/2015

Vaccine Biotechnology

Viruses Recombinant proteins Antibodies

Cover illustration


Special issue: Vaccine Biotechnology. This Special issue edited by Reingard Grabherr and Udo Reichl includes articles on the design of cell lines for viral vaccine production, downstream processing of virus-like particles and plant-based production of vaccines. The cover shows particles of highly pathogenic viruses transmitted by mosquitoes: Chikungunya, dengue and Rift Valley fever virus. Image by Gorben Pijlman.

Biotechnology Journal – list of articles published in the May 2015 issue.

Reingard Grabherr and Udo Reichl

Review Next generation vaccines and vectors: Designing downstream processes for recombinant protein-based virus-like particles

http://dx.doi.org/10.1002/biot.201500184

Christopher Ladd Effio and Jürgen Hubbuch

Editorial: Can modern vaccine technology pursue the success of traditional vaccine manufacturing?

Mini-Review Enveloped virus-like particles as vaccines against pathogenic arboviruses


Gorben P. Pijlman

Review Designing cell lines for viral vaccine production: Where do we stand?


Yvonne Genzel

Review Plant-made vaccines against West Nile virus are potent, safe, and economically feasible


Qiang Chen

Mini-Review Large-scale adenovirus and poxvirus-vectored vaccine manufacturing to enable clinical trials


Héla Kallel and Amine A. Kamen

Review Defective interfering viruses and their impact on vaccines and viral vectors



Research Article The fusion of Toxoplasma gondii SAG1 vaccine candidate to Leishmania infantum heat shock protein 83-kDa improves expression levels in tobacco chloroplasts

Review Emerging influenza viruses and the prospect of a universal influenza virus vaccine

Romina M. Albarracín, Melina Laguía Becher, Inmaculada Farran, Valeria A. Sander, Mariana G. Corigliano, María L. Yácono, Sebastián Pariani, Edwin Sánchez López, Jon Veramendi and Marina Clemente1

Timo Frensing

Florian Krammer


http://dx.doi.org/10.1002/biot.201400393 Review The baculovirus expression vector system: A commercial manufacturing platform for viral vaccines and gene therapy vectors

Research Article Human amniocyte-derived cells are a promising cell host for adenoviral vector production under serum-free conditions

Rachael S. Felberbaum

Ana Carina Silva, Daniel Simão, Claudia Küppers, Tanja Lucas, Marcos F. Q. Sousa, Pedro Cruz, Manuel J. T. Carrondo, Stefan Kochanek and Paula M. Alves





Research Article Adjuvant poly(N-isopropylacrylamide) generates more efficient monoclonal antibodies against truncated recombinant histidine-rich protein2 of Plasmodium falciparum for malaria diagnosis

Research Article Wheat enolase demonstrates potential as a non-toxic cryopreservation agent for liver and pancreatic cells

Reena Verma, Ramakrishnan Ravichandran, Naatamai S. Jayaprakash, Ashok Kumar, Mookambeswaran A.Vijayalakshmi, and Krishnan Venkataraman


http://dx.doi.org/10.1002/biot.201400386 Biotech Method Bacterial cytoplasmic display platform Retained Display (ReD) identifies stable human germline antibody frameworks Matthew D Beasley, Keith P Niven, Wendy R Winnall and Ben R Kiefel

Mélanie Grondin, Mélanie Chow-Shi-Yée, François Ouellet and Diana A. Averill-Bates

Biotech Method Purification and simultaneous immobilization of Arabidopsis thaliana hydroxynitrile lyase using a family 2 carbohydratebinding module Benita Kopka, Martin Diener, Astrid Wirtz, Martina Pohl, Karl-Erich Jaeger and Ulrich Krauss


http://dx.doi.org/10.1002/biot.201400560 Research Article Heat shock protein 27 overexpression in CHO cells modulates apoptosis pathways and delays activation of caspases to improve recombinant monoclonal antibody titre in fed-batch bioreactors Janice G.L. Tan, Yih Yean Lee, Tianhua Wang, Miranda G. S. Yap, Tin Wee Tan and Say Kong Ng




Novel universal influenza virus vaccine approaches.

Animal models for influenza viruses: implications for universal vaccine development.

Prospects of HA-based universal influenza vaccine.

Emerging respiratory viruses other than influenza.

Portraits of viruses: influenza virus A.

Options and obstacles for designing a universal influenza vaccine.

Universal biosensor for detection of influenza virus.

Conservation of T cell epitopes between seasonal influenza viruses and the novel influenza A H7N9 virus.

Swine influenza virus and the recycling of influenza-A viruses in man.

Mucosal immunization with a candidate universal influenza vaccine reduces virus transmission in a mouse model.

Novel Sequence-Based Mapping of Recently Emerging H5NX Influenza Viruses Reveals Pandemic Vaccine Candidates.

Towards a split influenza virus vaccine.

Toxicities of influenza vaccine: peripheral leukocytic response to live and inactivated influenza viruses in mice.

Influenza virus vaccine and egg allergy.

Immune response to inactivated influenza virus vaccine: antibody reactivity with epidemic influenza B viruses of two highly distinct evolutionary lineages.

FluKB: A Knowledge-Based System for Influenza Vaccine Target Discovery and Analysis of the Immunological Properties of Influenza Viruses.

Development of universal influenza vaccines based on influenza virus M and NP genes.

Antiviral strategies for emerging influenza viruses in remote communities.

Efficacy of Live-Attenuated H9N2 Influenza Vaccine Candidates Containing NS1 Truncations against H9N2 Avian Influenza Viruses.

Infection of influenza virus neuraminidase-vaccinated mice with homologous influenza virus leads to strong protection against heterologous influenza viruses.

Cats as a potential source of emerging influenza virus infections.

Transmission of influenza A viruses.

Sphingolipids of influenza viruses.

H7N9 influenza virus.