A recombinant option for flu pandemic

In 2018, the world marked the centenary of the devastating 1918-19 influenza pandemic, which claimed over fifty million lives. Today, as we grapple with the aftermath of the Covid-19 pandemic, the World Health Organisation (WHO) issues stark warnings about the looming threat of another influenza pandemic. Recent history bears witness to influenza pandemics in 1957-58, 1968-69, and 2009-2010. The inevitability of a future flu pandemic is a grim reality, exacerbated by increasing globalisation, global warming, urbanisation, and mobility.

These pandemics stem from the influenza virus’ capacity to infect multiple species and occasionally recombine, creating new infectious strains to which humans have little immunity.

A matter of time

Heightened concerns about potential human-to-human transmission arise from increasing H5N1 avian-origin influenza cases among mammals, (biologically closer to humans than birds). “Influenza pandemic in the future is a real risk, when is the big question,” says Dr Sylvie Briand Director of the Pandemic and Epidemic Diseases Department at the World Health Organisation.

Influenza viruses have circulated for centuries, causing severe illnesses, particularly among children, the elderly, pregnant women, and those with underlying health conditions. Globally, influenza results in an estimated one billion human
cases and 2,90,000 to 6,50,000 annual fatalities.

To combat the threat of influenza, Professor Raghavan Varadarajan of the Molecular Biophysics Unit at the Indian Institute of Science (IISc) collaborates with Dr Gautham Nadig as co-founders of Mynvax. Together, they are developing recombinant vaccines with improved efficacy compared to current vaccines and enhanced breadth of protection.

Since 1973, the World Health Organisation’s Global Influenza Surveillance and Response System (GISRS) has defined the composition of the seasonal influenza vaccines. Expert consultations occur biannually in February and September for the Northern and Southern hemispheres respectively, leading to annual vaccine updates.

When is flu season?

The Indian Council for Medical Research (ICMR) National Institute of Virology (NIV) in Pune, a WHO-designated national influenza centre, has diligently monitored influenza and other respiratory infections since 2004. NIV has identified two distinct peaks of influenza activity: one during monsoon (June-September) and another during winter (November-January). Dr Varsha Potdar, Influenza group leader at NIV, reveals that despite India’s northern hemisphere location, cities with temperate seasonality benefit from vaccinations in September-October, while cities experiencing flu peaks during the monsoon season, benefit from April-May vaccinations. Traditional flu vaccines rely on an egg-based manufacturing process, used for both inactivated (killed) vaccines (“flu shots”) and live attenuated vaccines (the “nasal spray flu vaccine”). However, inactivated vaccines developed during the Covid pandemic did not stimulate a robust immunogenic response. These vaccines lack the virus-killing potential mediated through a type of white blood cell called ‘T Lymphocytes,’ according to Dr Satyajit Rath, an immunology expert and emeritus professor at the Indian Institute of Science Education and Research (IISER) in Pune. Professor Jeffrey Almond, a vaccine expert from Oxford, notes that current flu vaccines offer limited protection (around 50-60%), contrasting with vaccines for diseases like mumps and measles, which boast of efficacy rates around 90%. This lower efficacy contributes to lower vaccine uptake in many communities.

Protein is key

Egg-based vaccines, while reliable, face challenges due to the massive quantities of hen eggs required, and this could get more challenging considering climate change, fears Dr Shahid Jameel, a noted virologist. Cell culture vaccines, the other vaccine platform, are expensive. Thus, developing a recombinant vaccine based on a single protein that can be scaled up during a pandemic is worth pursuing, pending efficacy studies. Explaining the technology behind their recombinant vaccine development, Dr Nadig and Prof Varadarajan elaborate that they first obtained the virus’ gene containing the genetic instructions for making HA (Haemagglutinins). HA is an antigen, a feature of the flu virus, which triggers the human immune system to create antibodies that specifically target the virus.

The HA gene is combined into a baculovirus, a type of virus that infects invertebrates. This HA-containing baculovirus is used to infect a particular type of insect cell line where it rapidly produces HA antigens in bulk, collected, and purified.

Thus, baculovirus is only used to deliver genetic instructions for making HA antigens in the cell, and the vaccine does not contain any virus in it.

Dr Satyajit Rath commends Mynvax’s earlier success in creating a temperature-stable Covid-19 vaccine formulation, now applied to influenza. A stable vaccine at extreme temperatures would be invaluable from an Indian perspective, states Dr Jameel.

Extensive analysis of 75 years of virus sequences from the database has led to the design of a conserved HA region. Coupled with strategies to enhance antigen yield and the use of an adjuvant (an ingredient used in vaccines to increase the response), this development is expected to result in a more effective vaccine.

The developers of the Mynvax vaccine are optimistic about its potential. Animal studies have demonstrated protection against diverse viruses dating back to 1934. Moreover, the recombinant vaccine overcomes limitations associated with relying on hen eggs, which could face shortages during a pandemic, and with the virus undergoing adaptation in the egg potentially reducing vaccine efficacy. Phase 1 trials are scheduled to commence in Australia later this year, with phase 2 and 3 trials planned in India for the following year. While a universal influenza vaccine remains a distant goal, achieving an average protective efficacy of about 70-80% against seasonal influenza would be a significant achievement, says Prof Varadarajan.

Prof Almond envisions that a more effective vaccine could boost vaccine production and uptake several billion doses seasonally, with a market reach of up to 30 to 40 billion dollars, potentially benefiting lower-income countries eventually.

(The author is a consultant haemato-oncologist with a special interest in stem cell transplantation at Royal Wolverhampton NHS Trust, UK. He can be reached at [e-mail])