Future Directions in Flu Vaccines

Lance JenningsCanterbury Health Laboratories & Pathology Department, University of

Otago, Christchurch

Outline

• Why we need to vaccinate against influenza• The burden of disease:

• Issues related to the virus & our immune response• Current vaccines• Vaccine challenges

• Antigenic & genetic drift• H3N2 viruses

• Next generation vaccines• The “Universal Vaccine”. ??? Solution for the future

Burden of DiseaseGlobal estimates

• New estimates from 47 countries (1995-2015)

• 291,243 to 645,832 deaths annually ~4-8.8/100,000 persons

• Highest in sub-Saharan Africa, SE Asia & persons older than 75 years (17.9-223.5/100,00 persons)

• In children <5 yrs: 9,243 - 105,690 deaths annually

• Ever present threat of pandemic influenza

Iuliano et al; Lancet, 2018

Mortality increases from age 50 years

New Zealand

ESR, 2017

Influenza viruses come in many flavours…

.. and many different host species

Hirimoto & Kawaoka, CMR, 2001

Haemagglutinin & Neuraminidase are the main targets of the protective antibody response

Course of immune response during influenza infection

Subbarao et al, Immunity (2006)24,5-9

Inactivated influenza vaccines• Trivalent or Quadrivalent formulations to protect against epidemic

influenza A and B viruses• Trivalent vaccines contain A/H1N1, A/H3N2 and one B strain • Quadrivalent vaccines contain A(H1N1), A(H3N2) ,B/Yamagata-lineage and

B/Victoria-lineage viruses• Response: Based on the serum antibody response to the haemagglutinin

(HA) protein• Principle: Induction of a protective antibody response against the HA

protein• Vaccination strategy:

• Individual protection• Indirect protection of others: healthcare workers (individual & ring-”duty of care”)

Inactivated influenza vaccines• Inactivated Influenza Vaccine (IIV) contains 15µg of each HA antigen

and is administered by intramuscular injection• Virus infectivity inactivated with formalin or betapropriolactone.• Virions are detergent-disrupted and the preparation is enriched for

glycoproteins (HA & NA) by centrifugation

• Trivalent “enhanced vaccines” available for use in people >65 years• High dose IIV containing 60ug of each HA• Adjuvanted IIV with an oil in water adjuvant

Cell Culture process

Egg-based process

Live attenuated influenza vaccines

• LAIV (Live Attenuated) - UK• Broader immune response (indicated for ages 2-49 years)• Better for children Advantage for herd immunity• ? Safety issues in children <2 yrs & immunocompromised

Other• Recombinant HA vaccines

• Produced in a recombinant–protein-expressing system (Insect cells, Baculovirus)• Lacks unwanted mutations, produced in 2 months (? Pandemic Vaccine)• Contains 3 X amount of HA antigen, = strain specific immunity• Limited to individuals 18-49 years

Egg-based LAIV

Currently licensed influenza vaccines• QIV (Quadrivalent): NZ schedule 2018

• TIV (Trivalent inactivated vaccines): NZ schedule since 1997

• hdTIV (High dose -4x) FluZone HD (Sanofi) Registered in USA & Canada• Stronger immune response in elderly• [22% reduction in risk of hospitalisation; Izurieta etal, NEJM 2000]

• aTIV (MF-59 Adjuvanted) FluAd (Seqirus) registered in ~30 countries• Expected to have stronger immune response• Used in some pandemic vaccines in 2009 (Safety issues –narcolepsy, local reactions)• Better immune response in elderly• [25% reduction risk for hospitalization; Mannino etal, J Amer Epidemiol 2012]

Challenges with influenza vaccines• Antigenic Drift

• Requires an update in vaccine composition• Challenge: About 50% of A/H3N2 viruses cannot be

isolated, or characterised in HAI tests

• Genetic Drift• Challenge: Enormous genetic diversity with several

clades and sub-clades co-circulating but few clades are associated wit antigenic difference in HAI assays

Antigenic drift

Yamayoshi & Kawaoka, Nature Medicine2019;25;212-220

WHO Vaccine Composition Recommendations for 2018/1019 Seasons

Influenza A/H3N2 viruses present the greatest challenge• Incidence of serious outcomes of influenza increased

in older people • 90% of deaths occur in older people• For every influenza death there are 3-4 influenza

hospitalisations• Greatest impact when A/H3N2 circulating• Response to vaccination decreased• Vaccine efficacy 70-90% in preventing respiratory

illness in healthy adults• Only 30-40% in older people, particularly for H3N2 strains• 8% decline in VE /month in older people

• BUT are cost saving, mainly due to prevention of A/H3N2 hospitalisation

2017 Case Test Negative data

ESR 2017

Challenges with influenza vaccines• >95% of global vaccine supply manufactured in embryonated eggs• Vaccines require months to manufacture

• Adaptation to growth in eggs induces mutations in the HA• Antibody responses induced by egg-grown vaccines react well with other egg-

grown viruses but not with cell-grown viruses• The sequence of cell-grown viruses resembles that of virus present in clinical sample

• Reduced effectiveness when vaccine and epidemic strains are antigenically mismatched

• Drift requires bi-annual reformulation & revaccination (?LMIC)• Antigenic shift requires a new vaccine component

• Most of currently licensed influenza vaccines generated in embryonated eggs• Cheapest option• Safest option

Next generation vaccinesWhy a “Universal Influenza Vaccine” strategy?

The virus is the problem? Potential Universal Vaccine Targets• Internal proteins• M2e• Neuraminidase (NA)• Stalk domain of

haemagglutinin (HA)• Conserved regions of

the head domain of HA

Krammer & Grabherr, Trends Mol Med, 2010

Internal proteins • Nucleoprotein (NP), M1 and polymerase subunits

• Conserved (i.e. About 90% aa identity for NP between human H1 & H3 isolates)

• Strong T-cell epitopes• Not easily accessible for antibodies

• Various experimental T-cell based vaccines with NP & M1 in animal models and clinical trials

• Vectored vaccines• NP+M1 expressing MVA vaccine was

able to induce strong CD8+ and CD4+ T-cell responses (Lillie et al, Clin Infect Dis 2012)

• Peptide vaccines• Multimeric-001 (BlondVax) contains

NP and M1 (Atsmon et al, J Clin Immunol, 2012)

M2e • 23 N-terminal aa’s which form the ectodomain of the tetrameric M2 ion channel

• Displayed on the cell surface, low copy number on the virus

• Conserved (~80% aa identity)• Early development of particle-based

M2e vaccines (Neirynck et al, Nat Med, 1999)

• Vaccination induces infection-permissive (non sterilising) immunity

• morbidity, virus replication• Mechanism

• Mainly Ab dependent cell mediated cytotoxicity (El Bakkouri et al, J Immunol 2011)

• Discussed as “additive” to regular influenza vaccine

Neuraminidase (NA)• Is expressed on the virus and on

infected cells• Drifts slower than HA, well conserved

within the subtype (i.e. within N1)• NA content not standardised in

commercial vaccines and there is barely any immune response to the NA that is present (Chen et al, Cell 2018)

• Human anti-NA antibody levels in humans correlate with protection

• Recombinant NA vaccines induce broad protection within the subtype (Wohlbold et al, mBio, 2015)

• Mechanism of protection: inhibition of enzymatic activity

Haemagglutinin (HA): parts are conserved

Krammer & Grabherr, Trends Mol Med, 2010

Antibodies against the influenza virus HA stalk domain

• Rare and not induced/boosted upon regular seasonal vaccination

• Have been isolated from humans & mice

• Cross-reactive between HAs of different subtypes

• Broad neutralising activity• Conformational epitopes• HAI negative

Cross-neutralising antibodies against Influenza virus HA

Chimeric HA technology

Krammer et al, Nature Immunol 2013 , ++

Headless HA

Progress with vaccine development?

• HA stalk• cHA vaccines (Phase I/II clinical trials)• Headless/mini HA (Johnson & Johnson Vaccine Research

Centre/NIH)• HA head

• COBRA (UGA/Sanofi Pasteur)• VLP combinations (NIH)• DNA vaccine combinations (Inovio)

• Internal proteins• MVA/AdV NP-M1 (Jenner Institute)• Peptide-based approach (BiondVax etc)

• M2e (multiple)• NA ???

Source: Krammer, Global Influenza Summit, Beijing, China Oct, 2018

NIAID Universal Vaccine Portfolio

Conclusions

• Current vaccines provide limited breadth• Universal vaccines are in early clinical trials and could

• Abolish the need for annual reformulation/vaccination• Make influenza virus vaccines globally available• Enhance pandemic preparedness

• Influenza B viruses can theoretically be eradicated• Progress is slow

• a Universal Vaccine is at least 5-10 years away