Uptake
At risk groups
Uptake of flu vaccination, both seasonally and during
pandemics, is often low. Systematic
reviews of pandemic flu vaccination uptake have identified several personal
factors that may influence uptake, including gender (higher uptake in men),
ethnicity (higher in people from ethnic minorities) and having a chronic
illness. Beliefs in the safety and
effectiveness of the vaccine are also important.
A number of measures have found to be useful to increase
rates of vaccination in those over 60 years old including: patient reminders
using leaflets and letters, postcard reminders, client outreach programs,
vaccine home visits, group vaccinations, free vaccinations, physician payment,
physician reminders and encouraging physician competition.
Healthcare workers
Frontline healthcare workers are often recommended to get
seasonal and any pandemic flu vaccination. For example, in the UK all
healthcare workers involved in patient care are recommended to receive the
seasonal flu vaccine, and were also recommended to be vaccinated against the
H1N1/09 (later renamed A(H1N1)pdm09[note 1) swine flu virus during the 2009
pandemic. However, uptake is often low. During the 2009 pandemic, low uptake by
healthcare workers was seen in countries including the UK, Italy, Greece, and Hong Kong.
In a 2010 survey of United States healthcare workers, 63.5%
reported that they received the flu vaccine during the 2010–11 season, an
increase from 61.9% reported the previous season. US Health professionals with
direct patient contact had higher vaccination uptake, such as physicians and
dentists (84.2%) and nurse practitioners (82.6%).
The main reason to vaccinate healthcare workers is to
prevent staff from spreading flu to their patients and to reduce staff absence
at a time of high service demand, but the reasons healthcare workers state for
their decisions to accept or decline vaccination may more often be to do with perceived
personal benefits.
In Victoria (Australia) public hospitals, rates of healthcare
worker vaccination in 2005 ranged from 34% for non-clinical staff to 42% for
laboratory staff. One of the reasons for rejecting vaccines was concern over
adverse reactions; in one study, 31% of resident physicians at a teaching
hospital incorrectly believed Australian vaccines could cause influenza.
Manufacturing
Flu vaccine is usually grown by vaccine manufacturers in fertilized
chicken eggs. In the Northern
hemisphere, the manufacturing process begins following the announcement
(typically in February) of the WHO recommended strains for the winter flu
season. Three strains (representing an
H1N1, an H3N2, and a B strain) of flu are selected and chicken eggs are
inoculated separately. These monovalent harvests are then combined to make the trivalent
vaccine.
As of November 2007, both the conventional injection and the
nasal spray are manufactured using chicken eggs. The European Union has also approved Optaflu,
a vaccine produced by Novartis using vats of animal cells. This technique is expected to be more scalable
and avoid problems with eggs, such as allergic reactions and incompatibility
with strains that affect avians like chickens. Research continues into the idea of a
"universal" influenza vaccine that would not require tailoring to a
particular strain, but would be effective against a broad variety of influenza
viruses. However, no vaccine candidates
had been announced by November 2007.
A DNA-based vaccination, which is hoped to be even faster to
manufacture, is, as of 2011,[needs update] in clinical trials, determining safety
and efficacy.
On November 20, 2012, Novartis received FDA approval for the
first cell-culture vaccine.
In a 2007 report, the global capacity of approximately 826
million seasonal influenza vaccine doses (inactivated and live) was double the
production of 413 million doses. In an aggressive scenario of producing
pandemic influenza vaccines by 2013, only 2.8 billion courses could be produced
in a six-month time frame. If all high- and upper-middle-income countries
sought vaccines for their entire populations in a pandemic, nearly 2 billion
courses would be required. If China pursued this goal as well, more than 3
billion courses would be required to serve these populations.[135] Vaccine
research and development is ongoing to identify novel vaccine approaches that
could produce much greater quantities of vaccine at a price that is affordable
to the global population.[citation needed]
Methods of vaccine generation that bypass the need for eggs
include the construction of influenza virus-like particles (VLP). VLP resemble
viruses, but there is no need for inactivation, as they do not include viral
coding elements, but merely present antigens in a similar manner to a virion.
Some methods of producing VLP include cultures of Spodoptera frugiperda Sf9
insect cells and plant-based vaccine production (e.g., production in Nicotiana
benthamiana). There is evidence that some VLPs elicit antibodies that recognize
a broader panel of antigenically distinct viral isolates compared to other
vaccines in the hemagglutination-inhibition assay (HIA).
Influenza vaccines are produced in pathogen-free eggs that
are 11 to 12 days old. The top of the egg is disinfected by wiping it with
alcohol and then the egg is candled to identify a non-veinous area in the
allantoic cavity where a small hole is poked to serve as a pressure release. A second hole is made at the top of the egg,
where the influenza virus is injected in the allantoic cavity, past the
chorioallantoic membrane. The two holes are then sealed with melted paraffin
and the inoculated eggs are incubated for 48 hours at 37 degrees Celsius. During
incubation time, the virus replicates and newly replicated viruses are released
into the allantoic fluid
After the 48-hour incubation period, the top of the egg is
cracked and the 10 milliliters of allantoic fluid is removed, from which about
15 micrograms of the flu vaccine can be obtained. At this point, the viruses
have been weakened or killed and the viral antigen is purified and placed inside
vials, syringes, or nasal sprayers. Done on a large scale, this method is used
to produce the flu vaccine for the human population.
In 2013, the recombinant influenza vaccine, Flublok, was
approved for use in the United States.
Annual reformulation
Each year, three strains are chosen for selection in that
year's flu vaccination by the WHO Global Influenza Surveillance and Response
System. The chosen strains are the H1N1, H3N2, and Type-B strains thought most
likely to cause significant human suffering in the coming season. Starting with
the 2012–2013 Northern Hemisphere influenza season (coincident with the
approval of quadrivalent influenza vaccines), the WHO has also recommended a
2nd B-strain for use in quadrivalent vaccines. The World Health Organization
(WHO) coordinates the contents of the vaccine each year to contain the most
likely strains of the virus to attack the next year.
"The WHO Global Influenza Surveillance Network was established in
1952 [renamed "Global Influenza Surveillance and Response System" in
2011]. The network comprises four WHO
Collaborating Centres (WHO CCs) and 112 institutions in 83 countries, which are
recognized by WHO as WHO National Influenza Centres (NICs). These NICs collect
specimens in their country, perform primary virus isolation and preliminary
antigenic characterization. They ship newly isolated strains to WHO CCs for
high level antigenic and genetic analysis, the result of which forms the basis
for WHO recommendations on the composition of influenza vaccine for the
Northern and Southern Hemisphere each year."
The Global Influenza Surveillance and Response System's
selection of viruses for the vaccine manufacturing process is based on its best
estimate of which strains will predominate the next year, amounting in the end
to well-informed but fallible guesswork.
Formal WHO recommendations were first issued in 1973.
Beginning in 1999 there have been two recommendations per year: one for the
northern hemisphere and the other for the southern hemisphere.
Historical annual reformulations of the influenza vaccine
are listed in a separate article. Recent WHO seasonal influenza vaccine
composition recommendations:
2017–2018 Northern
Hemisphere influenza season
The composition of trivalent virus vaccines for use in the
2017–2018 Northern Hemisphere influenza season recommended by the Advisory
Committee on Immunization Practices on August 25, 2017 was:
·
an A/Michigan/45/2015 (H1N1)pdm09–like
virus[note 1
·
an A/Hong Kong/4801/2014 (H3N2)-like virus
·
a B/Brisbane/60/2008–like virus (Victoria
lineage)
In addition to these components, quadrivalent vaccines will
also include a B/Phuket/3073/2013–like virus (Yamagata lineage).
In California, some emergency systems were strained by a
spike in H3N2 flu cases. In addition, some areas experienced local shortages of
oseltamivir. The severity of the flu
season seemed somewhat comparable to the 2009–10 swine flu outbreak. A February
2018 CDC interim report estimated the vaccine effectiveness to be 25% against
H3N2, 67% against H1N1, and 42% against influenza B.
2018 Southern
Hemisphere influenza season
The composition of virus vaccines for use in the 2018
Southern Hemisphere influenza season recommended by the World Health
Organization on September 28, 2017 was:
·
an A/Michigan/45/2015 (H1N1)pdm09-like
virus[note 1]
·
an A/Singapore/INFIMH-16-0019/2016 (H3N2)-like
virus
·
a B/Phuket/3073/2013-like virus
WHO recommended that quadrivalent vaccines containing two
influenza B viruses should contain the above three viruses and a B/Brisbane/60/2008-like
virus.
2018–2019 Northern
Hemisphere influenza season
The composition of virus vaccines for use in the 2018–2019
Northern Hemisphere influenza season recommended by the World Health
Organization on February 22, 2018 was:
·
an A/Michigan/45/2015 (H1N1)pdm09-like virus
·
an A/Singapore/INFIMH-16-0019/2016 (H3N2)-like
virus
·
a B/Colorado/06/2017-like virus (B/Victoria/2/87
lineage)
·
a B/Phuket/3073/2013-like virus
(B/Yamagata/16/88 lineage)
WHO recommended that trivalent vaccines use as their
influenza B virus a B/Colorado/06/2017-like virus of the B/Victoria/2/87-lineage. A February 2019, CDC interim report estimated
the vaccine effectiveness to be approximately 47% against the 2018–2019 flu
strains.
2019 Southern
Hemisphere influenza season
The composition of virus vaccines for use in the 2019
Southern Hemisphere influenza season recommended by the World Health Organization
in September 2018 was:
·
an A/Michigan/45/2015 (H1N1)pdm09-like virus
·
an A/Switzerland/8060/2017 (H3N2)-like virus
·
a B/Colorado/06/2017-like virus (B/Victoria/2/87
lineage)
·
a B/Phuket/3073/2013-like virus
(B/Yamagata/16/88 lineage)
WHO recommended that trivalent vaccines use as their
influenza B virus a B/Colorado/06/2017-like virus of the
B/Victoria/2/87-lineage.
2019–2020 Northern
Hemisphere influenza season
The composition of virus vaccines for use in the 2019–2020
Northern Hemisphere influenza season recommended by the World Health
Organization on March 21, 2019 was:
·
an A/Brisbane/02/2018 (H1N1)pdm09-like
virus[note 1]
·
an A/Kansas/14/2017 (H3N2)-like virus
·
a B/Colorado/06/2017-like virus (B/Victoria/2/87
lineage)
·
a B/Phuket/3073/2013-like virus
(B/Yamagata/16/88 lineage)
WHO recommended that trivalent vaccines use as their
influenza B virus a B/Colorado/06/2017-like virus of the B/Victoria/2/87-lineage.
2020 Southern
Hemisphere influenza season
The composition of virus vaccines for use in the 2020
Southern Hemisphere influenza season influenza season recommended by the World
Health Organization in September 2019 was:
·
an A/Brisbane/02/2018 (H1N1)pdm09-like virus
·
an A/South Australia/34/2019 (H3N2)-like virus
·
a B/Washington/02/2019-like (B/Victoria lineage)
virus
·
a B/Phuket/3073/2013-like (B/Yamagata lineage)
virus
WHO recommended that trivalent vaccines use as their
influenza B virus a B/Washington/02/2019-like (B/Victoria lineage) virus.
History
Vaccines are used in both humans and nonhumans. Human
vaccine is meant unless specifically identified as a veterinary, poultry or
livestock vaccine.
Origins and
development
In the worldwide Spanish flu pandemic of 1918,
"Physicians tried everything they knew, everything they had ever heard of,
from the ancient art of bleeding patients, to administering oxygen, to
developing new vaccines and serums (chiefly against what we now call Hemophilus
influenzae—a name derived from the fact that it was originally considered the
etiological agent—and several types of pneumococci). Only one therapeutic
measure, transfusing blood from recovered patients to new victims, showed any
hint of success."
In 1931, viral growth in embryonated hens' eggs was reported
by Ernest William Goodpasture and colleagues at Vanderbilt University. The work
was extended to growth of influenza virus by several workers, including Thomas
Francis, Jonas Salk, Wilson Smith and Macfarlane Burnet, leading to the first
experimental influenza vaccines. In the
1940s, the US military developed the first approved inactivated vaccines for
influenza, which were used in the Second World War. Hen's eggs continued to be used to produce
virus used in influenza vaccines, but manufacturers made improvements in the
purity of the virus by developing improved processes to remove egg proteins and
to reduce systemic reactivity of the vaccine.
The U.S. Food and Drug Administration (FDA) approved influenza vaccines
made by growing virus in cell cultures[168] and influenza vaccines made from
recombinant proteins have been approved, with plant-based influenza vaccines
being tested[when?] in clinical trials.
Acceptance
According to the CDC: "Influenza vaccination is the
primary method for preventing influenza and its severe complications. [...]
Vaccination is associated with reductions in influenza-related respiratory
illness and physician visits among all age groups, hospitalization and death
among persons at high risk, otitis media among children, and work absenteeism
among adults. Although influenza vaccination levels increased substantially
during the 1990s, further improvements in vaccine coverage levels are
needed".
The egg-based technology (still in use as of 2019) for
producing influenza vaccine was created in the 1950s. In the U.S. swine flu scare of 1976, President
Gerald Ford was confronted with a potential swine flu pandemic. The vaccination
program was rushed, yet plagued by delays and public relations problems.
Meanwhile, maximum military containment efforts succeeded unexpectedly in
confining the new strain to the single army base where it had originated. On
that base, a number of soldiers fell severely ill, but only one died. The
program was canceled after about 24% of the population had received
vaccinations. An excess in deaths of twenty-five over normal annual levels as
well as 400 excess hospitalizations, both from Guillain–Barré syndrome, were
estimated to have occurred from the vaccination program itself, illustrating
that the vaccine itself is not free of risks. The result has been cited to
stoke lingering doubts about vaccination. In the end, however, even the
maligned 1976 vaccine may have saved lives. A 2010 study found a significantly
enhanced immune response against the 2009 pandemic H1N1 in study participants
who had received vaccination against the swine flu in 1976.
Cost-effectiveness
The cost-effectiveness of seasonal influenza vaccination has
been widely evaluated for different groups and in different settings. In the elderly (aged over 65 years) the
majority of published studies have found that vaccination is cost saving, with
the cost savings associated with influenza vaccination (e.g. prevented
healthcare visits) outweighing the cost of vaccination. In older adults (aged 50–64 years), several
published studies have found that influenza vaccination is likely to be
cost-effective, however the results of these studies were often found to be
dependent on key assumptions used in the economic evaluations. The uncertainty
in influenza cost-effectiveness models can partially be explained by the
complexities involved in estimating the disease burden, as well as the seasonal
variability in the circulating strains and the match of the vaccine. In healthy working adults (aged 18–49 years),
a 2012 review found that vaccination was generally not cost-saving, with the
suitability for funding being dependent on the willingness to pay to obtain the
associated health benefits. In children,
the majority of studies have found that influenza vaccination was
cost-effective, however many of the studies included (indirect) productivity
gains, which may not be given the same weight in all settings. Several studies
have attempted to predict the cost-effectiveness of interventions (including
prepandemic vaccination) to help protect against a future pandemic, however
estimating the cost-effectiveness has been complicated by uncertainty as to the
severity of a potential future pandemic and the efficacy of measures against
it.
Research
Influenza research includes molecular virology, molecular
evolution, pathogenesis, host immune responses, genomics, and epidemiology.
These help in developing influenza countermeasures such as vaccines, therapies
and diagnostic tools. Improved influenza countermeasures require basic research
on how viruses enter cells, replicate, mutate, evolve into new strains and
induce an immune response. The Influenza Genome Sequencing Project is creating
a library of influenza sequences that will help researchers' understanding of
what makes one strain more lethal than another, what genetic determinants most
affect immunogenicity, and how the virus evolves over time. Solutions to
limitations in current vaccine methods are being researched.
A different approach uses Internet content to estimate the
impact of an influenza vaccination campaign. More specifically, researchers
have used data from Twitter and Microsoft's Bing search engine, and proposed a
statistical framework which, after a series of operations, maps this
information to estimates of the influenza-like illness reduction percentage in
areas where vaccinations have been performed. The method has been used to
quantify the impact of two flu vaccination programmes in England (2013/14 and
2014/15), where school-age children were administered a live attenuated
influenza vaccine (LAIV). Notably, the impact estimates were in accordance with
estimations from Public Health England based on traditional syndromic surveillance
endpoints.
Rapid response to pandemic
flu
The rapid development, production, and distribution of
pandemic influenza vaccines could potentially save millions of lives during an
influenza pandemic. Due to the short time frame between identification of a
pandemic strain and need for vaccination, researchers are looking at novel
technologies for vaccine production that could provide better
"real-time" access and be produced more affordably, thereby
increasing access for people living in low- and moderate-income countries,
where an influenza pandemic may likely originate, such as live attenuated
(egg-based or cell-based) technology and recombinant technologies (proteins and
virus-like particles). As of July 2009, more than 70 known clinical
trials have been completed or are ongoing for pandemic influenza vaccines. In September 2009, the FDA approved four
vaccines against the 2009 H1N1 influenza virus (the 2009 pandemic strain), and
expected the initial vaccine lots to be available within the following month.
Quadrivalent vaccines
for seasonal flu
A quadrivalent flu vaccine administered by nasal mist was
approved by the FDA in March 2012. Fluarix Quadrivalent was approved by the FDA
in December 2012.
Universal flu
vaccines
A "universal vaccine" that would not have to be
designed and made for each flu season in each hemisphere would be useful, in
order to stabilize the supply and to ensure against error in the design or
escape of the circulating strains by mutation. Such a vaccine has been the subject of
research for decades.
One promising approach is using broadly neutralizing
antibodies that unlike the vaccine used today, which provoke the body to
generate an immune response, instead provide a component of the immune response
itself. The first neutralizing antibodies were identified in 1993, via
experimentation; with time researchers understood that the flu neutralizing
antibodies were binding to the stalk of the Hemagglutinin protein; later
researchers identified antibodies that could bind to the head of those
proteins. Later yet, researchers identified the highly conserved M2 proton
channel as a potential target for broadly neutralizing antibodies.
The challenges for researchers have been identifying single
antibodies that could neutralize many subtypes of the virus, so that they could
be useful in any season, and that target conserved domains that are resistant
to antigenic drift.
Another approach has been taking the conserved domains
identified from these projects, and delivering groups of these antigens to
provoke an immune response; various approaches with different antigens,
presented different ways (as fusion proteins, mounted on virus-like particles,
on non-pathogenic viruses, as DNA, and others), are under development.
Efforts have also been undertaken to develop universal vaccines
that specifically activate a T-cell response, based on clinical data showing
that people with a strong, early T-cell response have better outcomes when
infected with influenza and because T-cells respond to conserved epitopes. The
challenge for developers is that these epitopes are on internal protein domains
that are only mildly immunogenic.
Along with the rest of the vaccine field, people working on
universal vaccines have been experimenting with vaccine adjuvants to improve
the ability of their vaccines to create a sufficiently powerful and enduring
immune response.
As of 2019, there were some ongoing clinical trials of the
M-001 universal influenza vaccine candidate and the H1ssF_3928 universal
influenza vaccine candidate.
Veterinary use
Veterinary influenza vaccination aims to achieve the
following four objectives:
·
Protection from clinical disease
·
Protection from infection with virulent virus
·
Protection from virus excretion
·
Serological differentiation of infected from
vaccinated animals (so-called DIVA principle).
Horses
Horses with horse flu can run a fever, have a dry hacking
cough, have a runny nose, and become depressed and reluctant to eat or drink
for several days but usually recover in two to three weeks. "Vaccination
schedules generally require a primary course of two doses, 3–6 weeks apart,
followed by boosters at 6–12 month intervals. It is generally recognized that
in many cases such schedules may not maintain protective levels of antibody and
more frequent administration is advised in high-risk situations."
It is a common requirement at shows in the United Kingdom
that horses be vaccinated against equine flu and a vaccination card must be
produced; the International Federation for Equestrian Sports (FEI) requires
vaccination every six months.
Poultry
Poultry vaccines for bird flu are made inexpensively and are
not filtered and purified like human vaccines to remove bits of bacteria or
other viruses. They usually contain whole virus, not just hemagglutinin as in
most human flu vaccines. Another difference between human and poultry vaccines
is that poultry vaccines are adjuvated with mineral oil, which induces a strong
immune reaction but can cause inflammation and abscesses. "Chicken
vaccinators who have accidentally jabbed themselves have developed painful
swollen fingers or even lost thumbs, doctors said. Effectiveness may also be
limited. Chicken vaccines are often only vaguely similar to circulating flu
strains — some contain an H5N2 strain isolated in Mexico years ago. 'With a
chicken, if you use a vaccine that's only 85 percent related, you'll get
protection,' Dr. Cardona said. 'In humans, you can get a single point mutation,
and a vaccine that's 99.99 percent related won't protect you.' And they are
weaker [than human vaccines]. 'Chickens are smaller and you only need to
protect them for six weeks, because that's how long they live till you eat
them,' said Dr. John J. Treanor, a vaccine expert at the University of
Rochester. Human seasonal flu vaccines contain about 45 micrograms of antigen,
while an experimental A(H5N1) vaccine contains 180. Chicken vaccines may
contain less than one microgram. 'You have to be careful about extrapolating
data from poultry to humans,' warned Dr. David E. Swayne, director of the
agriculture department's Southeast Poultry Research Laboratory. 'Birds are more
closely related to dinosaurs.'"
Researchers, led by Nicholas Savill of the University of
Edinburgh in Scotland, used mathematical models to simulate the spread of H5N1
and concluded that "at least 95 percent of birds need to be protected to
prevent the virus spreading silently. In practice, it is difficult to protect
more than 90 percent of a flock; protection levels achieved by a vaccine are
usually much lower than this." The
Food and Agriculture Organization of the United Nations has issued
recommendations on the prevention and control of avian influenza in poultry,
including the use of vaccination.
A filtered and purified Influenza A vaccine for humans is
being developed[when?] and many countries have recommended it be stockpiled so
if an Avian influenza pandemic starts jumping to humans, the vaccine can
quickly be administered to avoid loss of life. Avian influenza is sometimes
called avian flu, and commonly bird flu.
Pigs
Swine influenza vaccines are extensively used in pig farming
in Europe and North America. Most swine flu vaccines include an H1N1 and an
H3N2 strain.
Swine influenza has been recognized as a major problem since
the outbreak in 1976. Evolution of the virus has resulted in inconsistent
responses to traditional vaccines. Standard commercial swine flu vaccines are
effective in controlling the problem when the virus strains match enough to
have significant cross-protection. Customised (autogenous) vaccines made from
the specific viruses isolated, are made and used in the more difficult cases. The
vaccine manufacturer Novartis claims that the H3N2 strain (first identified in
1998) has brought major losses to pig farmers. Abortion storms are a common
sign and sows stop eating for a few days and run a high fever. The mortality
rate can be as high as 15 percent.
Dogs
In 2004, influenza A virus subtype H3N8 was discovered to
cause canine influenza. Because of the lack of previous exposure to this virus,
dogs have no natural immunity to this virus. However, a vaccine was found in
2004.