BARDA and its industry partners have made tremendous strides to build better, faster, and more flexible vaccine technologies to enable the right vaccine to be where we need it, when we need it. Combating this age-old problem is an epic challenge, and there is still work to be done to speed availability of life-saving vaccines in a pandemic.

In September 1918, a doctor stationed at Camp Devens, a military base located near Boston, Massachusetts, wrote a letter to a colleague:

This epidemic started about four weeks ago and has developed so rapidly that the camp is demoralized….These men start with what appears to be an attack of la grippe or influenza, and when brought to the hospital they very rapidly develop the most vicious type of pneumonia that has ever been seen…. It is only a matter of a few hours then until death comes, and it is simply a struggle for air until they suffocate. It is horrible.

That local epidemic was part of the great influenza pandemic of 1918 that is estimated to have infected nearly one third of the world’s population – roughly 500 million people. The infections caused by the virus responsible for the pandemic were particularly deadly, killing more than 2.5 percent of those it infected, compared to most influenza viruses, which typically kill less than 0.1 percent of those infected. Estimates of the death toll range from 50 million to as high as 100 million people. Although most influenza deaths typically occur in children and the elderly, the 1918 virus struck down mostly healthy young adults between the ages of 20 and 40.

Scientists also believe that secondary bacterial infections contributed to the large numbers of deaths in what is usually a healthy population. The lack of vaccine to prevent infections and the lack of available treatments for influenza, along with secondary bacterial infections, left the entire world vulnerable to this virus.

Influenza viruses are known for their rapid changes and global spread. Influenza viruses that typically circulate seasonally can undergo small changes that can render a virus less recognizable to the human immune system, which relies on a prior immune response. The viruses can also change dramatically, leaving human populations immunologically naïve to these new viruses. If adapted to humans, these viruses can spread quickly from person to person and cause severe sickness and death.

A contributing factor to the virus’s rapid spread during 1918 was World War I. It provided a level of mobility not previously seen, as infected military troops carried the virus with them around the globe. An estimated 35,000 United States soldiers and sailors died from influenza.

Twenty years after the 1918 pandemic, researchers Jonas Salk and Thomas Francis developed the first vaccine against influenza. That early vaccine was produced using fertilized chicken eggs – the most advanced technology of its time – and was first used to protect American troops mobilizing during World War II.

Optimized for manufacturing speed and reliability, egg-based influenza vaccine production is still used today and is an important component of domestic pandemic preparedness. During egg-based vaccine production, manufacturers inject influenza virus into fertilized eggs. These eggs are incubated for several days to allow the virus to replicate. Then, the replicated virus is harvested, purified, and tested. Egg-based vaccine production relies on a readily-available supply of hundreds of millions of chicken eggs (one egg can produce enough virus to make two or three doses of pandemic vaccine) and usually takes about six months.

BARDA has also supported the development of additional influenza vaccine production technologies, which are now licensed and used in seasonal vaccines. These technologies that do not use eggs may hold several advantages to traditional egg-based vaccines, including faster production times.

One such technology is the use of cultured mammalian cells (“cell-based”). During cell-based vaccine production, manufacturers introduce the influenza virus onto the cultured cells, and the virus is allowed to replicate over a period of a few days. The rest of the process is very similar to that used for egg-based vaccine production. The first U.S. cell-based influenza vaccine was licensed by the FDA in November 2012, and a U.S. cell-based manufacturing facility was approved by the FDA in June 2014. Cell-based production can be done in less time than traditional egg-based production and, of course, does not rely on eggs, which can be a rare and vulnerable starting material during a pandemic.

Recombinant production methods are also used to produce a licensed influenza vaccine. This method can produce vaccine much faster than egg- or cell-based production – taking only about six to eight weeks – and doesn’t rely on a living influenza virus. In recombinant technology, manufacturers take genetic sequences from the influenza virus of concern and use this to make the vaccine. No eggs are needed, nor is there a need to rely on growth variability of influenza viruses. The sequence provides the information that the cell needs to produce the vaccine protein. From there the rest of the process is similar to that used for egg- or cell-based vaccine production. Recombinant technologies are fast and may allow for greater flexibility as a vaccine production platform, so that we are able to respond quickly to other emerging disease threats.

BARDA’s support for enhancing domestic vaccine manufacturing production, and the development of other technologies to produce influenza vaccines has diversified, expanded and enhanced the influenza vaccine market. We are learning more every day about the advantages of these newer technologies.

However, there is more to be done. In addition, there are methods that can improve the effectiveness of our current vaccines, including exploring higher doses and the addition of adjuvant. Our colleagues at the National Institutes of Health continue to pursue the promise of universal influenza vaccines, and BARDA is working hard to make vaccines that are more effective and can be produced more rapidly. BARDA also continues to develop and maintain the National Pre-pandemic Influenza Vaccine Stockpile (NPIVS) of vaccine against influenza viruses with pandemic potential. In addition to providing faster vaccine options in the event of the spread of these viruses, the NPVS has also allowed for continued research on these vaccines.

Medical advances since 1918 have provided us with tools to fight influenza. However, a more mobile global population and ever-changing viruses present daunting challenges. In order to save lives and protect Americans in a pandemic, BARDA will continue to advance modern, rapid ways to identify influenza viruses and to produce effective influenza vaccines and treatment options against these newly emerging viruses, an essential component to saving lives.