The most common way that flu vaccines are made is using
an egg-based manufacturing process that has been used for
more than 70 years.
In this process, the CDC, or one of their laboratory
partners, provides pharmaceutical companies with candidate
vaccine viruses grown in eggs. These virus are then injected
into fertilized hen’s eggs and incubated for several days to
allow the viruses to replicate. Eventually, the virus-containing
fluid is harvested from the eggs and the influenza viruses are
inactivated, purified and tested for use in the vaccine.
There are some strains of the flu that present challenges
within egg-based manufacturing, particularly H3N2. These
viruses are difficult to propagate in eggs, and sometimes, the
virus even changes during the process.
Egg-based manufacturing is particularly problematic
during a pandemic.
The last pandemic began in March 2009 when, at the end
of the flu season, a new strain emerged in California and
Mexico. By April it had spread to the rest of the world.
The strain was isolated right away, but because it takes six
months to grow a virus in eggs, the vaccine would not be
ready until October. Still, officials felt confident that, because
viruses tend to peak in December and January, that the vaccine would be ready in time to treat a pandemic, said Fauci.
“We felt reasonably sure that by the time this inevitable
pandemic came we would have doses,” he said. “However, in
September 2009 we had the beginning of the pandemic as
soon as the children came back to school. The cases began to
peak in the early fall, and we didn’t get our vaccine doses until
the late fall. So what we had was a vaccine that was far too late
to be of substantial help.”
Making improvements on
While approximately 70 percent of flu vaccines are still made
using eggs, other methods are coming to the forefront.
In 2016, the FDA issued an approval for Seqirus, the
first cell-based flu vaccine manufacturer in the U.S., to use
cell-grown vaccine viruses. In this method, the viruses are
cultured into mammalian cells and allowed to replicate for a
few days. Then, the virus-containing fluid is collected from
the cells and the virus antigen is purified.
However, this approach still has limitations, said Fauci.
“I, and many of my colleagues, think that this still is not good
enough,” said Fauci. “What we really need to do is get to the
point where you never have to grow a virus to make a vaccine.
You clone it, you put it in whatever vector you want to put it in,
so you don’t need to wait for a seven month process to grow it.”
Strides toward this goal have been achieved. The FDA ap-
proved the first recombinant influenza vaccine, Flublok Quad-
rivalent, which is manufactured by Sanofi Pasteur, in 2013.
In this production method, manufacturers isolate a certain
gene known as the hemagglutinin (HA) gene from a naturally
occurring “wild type” recommended vaccine virus. This HA gene
is then combined with portions of another virus that grows well
in insect cells. This recombinant vaccine virus is then mixed with
insect cells and allowed to replicate in these cells. The flu HA
protein is then harvested from these cells and purified.
The quest for a universal vaccine
While it is critical that research continues that is focused
on improving current seasonal vaccines and preventing
pandemics, the ultimate goal should be to create a universal
flu vaccine that protects patients against multiple strains of flu.
This won’t happen all at once, but in stages, said Fauci,
“To achieve a universal flu vaccine it is going to be a multi-
ple step process, it’s not going to happen overnight, and we
aren’t going to get to total universality right from the begin-
ning. In fact, we might not ever get to total universality.”
Fauci and his colleagues at NIAID unveiled their strategic
plan to make this happen, which was published in The Journal
of Infectious Diseases in July 2018.
To develop a universal influenza vaccine, the NIAID plan
states that the organization will focus resources on three key
areas of influenza research: improving the understanding of
the transmission, natural history and pathogenesis of influenza
infection; precisely characterizing how protective influenza immunity occurs and how to tailor vaccination responses to achieve
it; and supporting the rational design of universal influenza
vaccines, including designing new immunogens and adjuvants to
boost immunity and extend the duration of protection.
STEPS TOWARDS A UNIVERSAL
Credit: Oxford University Press for the
Infectious Diseases Society of America, 2018