Infuenza Virus and Development of "Universal Flu Vaccine"
Influenza virus can cause seasonal or pandemic influenza infections. WHO estimates that influenza has caused 3-5 million severe infections, with 250,000-500,000 deaths globally/year. During the 2017-2018 flu season, there were 810,000 hospitalizations and 61,000 flu related deaths in the United States. In 2019, there were 217,000 laboratory confirmed flu cases in Australia, with 430 deaths. Influenza viruses tend to cause severe infections in children younger than 5 and in the aged population above 65. Deaths in these two groups of individuals are often due to lack of vaccination and weak immune responses.
Influenza A and B viruses co-circulate and cause the seasonal epidemics. Current vaccines are either inactivated (Fluzone, Fluarix ) or sub-unit (Flublok) vaccines. Inactivated influenza viruses are cultivated in eggs and only a small number (Flucelvax) are grown in MDCK cell cultures. Egg-based vaccines have several limitations such as the availability of vaccine quality eggs, time consuming manufacturing process (6 months) which can lead to vaccine shortage and manufacturers may not have the flexibility in the number of doses produced. The WHO, CDC and NIH are tasked with projecting the flu strains to be incorporated every year for the seasonal flu vaccine. Inactivated influenza vaccine (IIV) is approved for children 6 months and older including pregnant women and persons with chronic medical conditions. Inactivated quadrivalent vaccines comprising two influenza A subtypes and two influenza B lineages are recommended for children and adults. Trivalent vaccines contain two influenza subtypes and only one influenza B lineage.
The CDC reported the efficacy of seasonal flu vaccines during the 2012-2013 was only at 32% among adults aged 65. For 2018, the enhanced trivalent inactivated vaccine, TIV, were recommended for adults over 65. The efficacy of inactivated TIV is approximately 59% but could drop to 43% for those over 65. For the 2019-2020 season, the vaccine strains recommended were different variants of the H1N1 and H3N2 lineage of Influenza A viruses (IAV) and one or two lineages of Influenza B viruses (IBV). The inactivated vaccines provide strain specific antibody protection which is shortlived and the low efficacy of the IIV could be due to mismatched circulating and vaccine strains.
Another type of influenza vaccine, the live attenuated influenza vaccine (LAIV) was licensed in 2003 in the USA and is administered as a single dose nasal spray to those from 2-49 years of age with no underlying medical conditions. It is unsuitable for pregnant women but is highly recommended for children <3 years old. LAIV vaccine strains are cold adapted, temperature sensitive and are derived from attenuated master donor virus (MDV). LAIVs are restricted to replicate in the lower temperatures of the upper airways and cannot replicate in the warmer lower respiratory tracts. Thus, it is safe the efficacy of LAIV has been unexpectedly low in comparison with IIV, especially in the 2014-2015 flu season. This led to the USA Advisory Committee on Immunization Practices (ACIP) to withdraw its preferential recommendation of LAIV to young children. The manufacturer explained that the H1N1 strain used had a temperature sensitive mutation and it was rectified by using a new H1N1 strain from 2016. In the 2014-2015 flu season, 80% of the circulating Influenza A(H3N2) had drifted from the recommended Influenza A(H3N2) used in the LAIV. All the current LAIVs were derived from strains that were isolated from 1957 and 1960 and they do not resemble current circulating Influenza viruses. If LAIV is to be used, there is a need to continue development of new LAIVs based on currently circulating pandemic Influenza strains.
Influenza pandemics caused by Influenza A viruses can also emerge at unpredictable intervals which could significantly increase morbidity and mortality when compared with seasonal influenza. In 1918, 1957, 1968 and 2009, four influenza pandemics have occurred and claimed millions of lives. Additionally, in recent years, influenza viruses from avian (H5N1, H7N9 and H9N2), swine (H1N1, H1N2 and H3N2) and other zoonotic influenza viruses have caused more human infections and mortalities compared to the past decades.
"In 1918, 1957, 1968 and 2009, four influenza pandemics have occurred and claimed millions of lives."
There is a worry that viral drifts and shifts might allow transmission from animals to humans and caused the next influenza pandemic. For producing both the inactivated and live attenuated influenza vaccines, there is a continual need for annual strain updates and constraints of time needed to produce the two types of vaccines in eggs. Sometimes after a seasonal flu vaccine is formulated, the late arrival of a pandemic strain such as influenza A(H1N1) strain could render the seasonal flu vaccine ineffective. Instead of creating vaccines that target specific flu strains every year, can scientists create a "Universal Vaccine" that can provide at least 75% protection against Group 1 and Group II Influenza A viruses and with at least 1-year protection against all age groups? The Haemagglutinin (HA) protein on the surface of the Influenza virus mutates rapidly and this is why seasonal flu vaccines must be produced to be targeting against different HAs every season. The HA is composed of the globular head and a stalk domain. The Head domain (HA globular head) proteins are highly variable and immunologically dominant but the HA stalk (Stem) domain proteins are more conserved and immunologically subdominant. Headless HA strategy using mutants lacking the head and contained just the stalk was not effective for efficient cross protection of both HA Groups 1 and 2. Another HA stalk-based approach is based on chimeric HA which is consisted of the stalk domain derived from major target strains such as H1, H3 or B-viruses and fused head domain from irrelevant avian strains such as H5, H6 or H8. The chimeric HA approach uses a full length functional HA protein suitable for expression in the live attenuated viruses. The breath and efficacy of crossprotection conferred by HA stalk, chimeric stalk-based vaccine and H1-stabilized stem ferritin vaccines require further human challenge models.
The most advanced phase III “Universal Vaccine” candidate is the Biondvax’s M-001 while the plant derived Medicago’s MT-2271 (Virus like particle) vaccine has completed two randomized phase II clinical trials in 2019. A phase III randomized clinical trial involving the M-001 recombinant protein vaccine based on the multi-epitope approach is underway and is expected to complete by mid-2020. Although several novel vaccine technology platforms are promising for the development of a universal influenza vaccine, it is obvious that none of the pre-clinical or early clinical trials can mimic the real situation of a pandemic. Therefore, future studies might need to incorporate either inactivated or live attenuated vaccines for boosting possible heterologous protection. In addition, for newly emerging viruses from pandemics, selection of conserved B-cell antigens and T-cell epitope predictive algorithms could provide rational approaches for the design and development of a multi-epitope based peptide or expressed as a recombinant subunit vaccine.
