Influenza Vaccine: Discovery, Side Effects, and Future Research

This report provides a comprehensive literature review of the influenza vaccine. It begins with an introduction to influenza, detailing the virus, its transmission, and the different types (A, B, and C). The report then discusses the development and format of the influenza vaccine, including trivalent and quadrivalent formulations, and the importance of vaccination in preventing severe complications. The effectiveness of the vaccine, its side effects, and its impact on disease rates are analyzed, referencing various studies. The review also explores improvements in vaccine formulation, including recombinant proteins, cold-adapted influenza vaccines, genetically engineered vaccines, and universal vaccines. The report emphasizes the need for new vaccine types that are more reliable, effective, and rapid, with advanced production technology to increase surge capacity in pandemic situations. The analysis of the influenza vaccine concludes with the current limitations of existing vaccines, and directions for future research and development.

Running Head: INFLUENZA
Influenza
Name of the Student
Name of the University
Author Note

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Introduction
The paper deals with the literature review of the Influenza vaccine. In response to viral
infection, the vaccination developed against it is discussed. A through literature review is
performed to discuss the discovery of vaccine and its format. The paper also highlights the side
effects of the vaccination. The impact of the vaccination on various disease rates has been
discussed. Further research in this area and improvement in the vaccine formulation has been
comprehensively discussed.
Influenza- disease details
Influenza is an infectious disease also known as flu that effects the respiratory system.
Influenza viruses are the RNA virus, of Orthomyxoviridae family, which affects the birds and
mammals. This infection is characterised by the symptoms including severe headache, muscle
pain, coughing, sore throat, chills, fever and fatigue. It is typically transmitted by direct contact
with contaminated surfaces, bird droppings, and nasal secretions and is transmitted by air via
virus containing aerosols, sneezes, and coughing. The mode of transmission is not absolutely
clear. However, airborne aerosols are mostly responsible for infections in majority of cases.
There are three types of Influenza viruses that are known to infect humans. It includes influenza
A, B and C. The most common circulating types of influenza viruses are A and B. People with
weakened immunity, elderly and young children are prone to this infection. They are thus
classified as high risk population. Death due to influenza occurs in seasonal epidemics and result
in 3-5 million cases according to WHO. Each year 250000–500000 deaths due to influenza are
reported globally (Soema et al., 2015).

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There are number of tests available to diagnose influenza. It includes serology, vial
culture, reverse transcription polymerase chain reaction, rapid antigen testing, rapid molecular
assays and immunofluoresence assays. The results of these diagnostic tests should be evaluated
in reference to other epidemiological and clinical data accessible by the heath care providers.
Even in case of negative results, the infection may still persist. The accurate testing seems to be
reverse transcription polymerase chain reaction, for detecting the viral RNA (Vemula et al.,
2016).
Influenza vaccine
Vaccines are the effective way to prevent the seasonal and pandemic flu effects. Public
acceptance to the vaccination has been found to be moderate inspite of its efficacy in reducing
the mortality and morbidity. Vaccination is important to eliminate the serious consequences of
the viral infection including pneumonia, bronchitis, secondary bacterial infections,
cardiovascular infections and acute respiratory distress. These complications may lead to death if
left untreated and scientific studies have revealed that it remains a global threat to this day
(Darvishian et al. 2014).
The effectiveness of the viral vaccine depends on the age and health of the patients and
varies from season to season. Its efficacy also depends on the match of the antigens on the
vaccine strains with that of the circulating strains. However, the exact method to determine the
efficacy of vaccine effectiveness is debateable (Simonsen et al. 2007). Public perceives that the
illness caused by the Influenza virus is similar to the illness caused by the respiratory pathogens.
Since it appears to be similar disease, the public perceive that vaccination would be ineffective
consequently reducing its uptake by the patients. It is necessary to know the relative

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contributions of the influenza and other respiratory infections to “influenza like illness”. This
data must be collected in the context of older community-dwelling adults (Van Beek et al.,
2017).
The burden of infection and preventing it becomes more challenging with the secondary
bacterial infections. The immune response to the vaccination decrease with the age due to
immunosenescence (Haq & McElhaney, 2014). A lower antibody response in older people (65
years or more) is observed when compared to younger adults. In order to reduce the burden of
disease, there is need of developing influenza vaccine that will offer enhanced immunogenicity
in older patients. One of the effective means to increase the immunogenicity is to target efficient
intradermal vaccination route (Holland et al. 2008). This will ensure best outcomes in the
vulnerable population.
The format of the vaccine
According to Soema et al., (2015) the current influenza vaccine are trivalent
formulations, which contain inactivated influenza antigens. These vaccines are derived from two
influenza A strains and one influenza B strain. Recently, quadrivalent influenza vaccines have
joined this formulations containing an additional strain of influenza B. The first strain is A
(H1N1): an A/Michigan/45/2015 (H1N1)pdm09 - like virus. It is the new strain different from
that developed in 2016. The other A strain (H3N2) is A/Hong Kong/4801/2014 (H3N2) - like
virus. The first B strain is like B/Brisbane/60/2008 virus and the second B strain is like
B/Phuket/3073/2013 virus that is added to make the formulation quadrivalent.
The four vaccines are as follows-
1. Fluarix® Tetra (GSK)- administered to 3 years old and above

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2. FluQuadri® (Sanofi Pasteur)- administered to 3 years old and above
3. FluQuadri Junior® (Sanofi Pasteur) for children from 6 months-3years of age
4. Afluria Quad® (Seqirus)- administered to 18 years and above
These triavent and quaadrivalent vaccine injections contains the inactivated form of the
virus. The nasal spray formulations contain live attenuated influenza vaccine. It is the attenuated
or weak form of virus.
The format of the vaccine is to contain error-prone polymerase. It helps to accumulate
genetic mutations. These are selected for hemagglutinin (HA) and neuraminidase. The later is the
major glycoproteins on the viral surface. This format of vaccine mediates protection in body
thorough HA-specific antibodies. T cell responses and antibodies against NA reduces disease
severity (Soema et al., 2015).
Accordig to Darvishian et al. (2014) the risk of pneumonia, and subsequent death due to
hospitalisation were found reduced by many studies. For meta-analysis the author reviewed
cohort observational studies that conducted mortality assessment. Further, the author also
considered 1 randomized, double-blind, placebo-controlled trial and cost-effectiveness studies of
the vaccine ranged from 32% to 45% reducing pneumonia and hospitalisation. The efficacy to
reduce deaths due to influenza and pneumonia in hospitals ranged from 31% to 65%. The
vaccine was found 43% to 50% effective against respiratory condition that caused hospital
deaths. In addition this vaccine was also effective in preventing deaths from all causes. The
results from the randomise trials showed 50% efficacy of the vaccine in decreasing the in
influenza-related illness. The results from the cost effective studies highlighted the influenza
vaccine is effective in preventing the mortality and morbidity associated with the disease. Thus,
this vaccine is concluded to be cost savior for each person vaccinated per year.

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Side effects of vaccine
The author of the paper “clinical safety data management: definitions and standards for
expedited reporting e2a” reported adverse effects of the influenza vaccine. The data was
recorded according to the ICH experts (International Conference on Harmonisation). The experts
reported that influenza vaccine caused adverse events (ICH Harmonised Tripartite Guideline,
2017). The vaccine has side effects that are regarded as solicited systemic reactions. It includes
headache, fever, chills, malaise and, myalgia. The injection site reactions solicited are erythema,
induration, pain, ecchymosis, swelling, and pruritus. These adverse reactions were recorded for
seven days after vaccination. In some cases reactions were recorded after 28 days of vaccination
a even serious adverse events were observed by experts after six months of vaccination
(DiazGranados et al., 2015).
The injection site reactions were further graded as per the size of the are affected. The
swelling, erythema, ecchymosis, and induration,were recognized as grade 1 if <2.5 cm, and if
≥2.5 to <5 cm they were regarded as graded 2, and grade 3 if>5 com. Fever of grade 1 was
identified with body temperature of ≥37.5 ◦C to ≤38 ◦C, grade 2 with further rise in tempertaire
and 3 with temperature greater than 39◦C. If the systemic reaction both solicited and unsolicited
were noticeable then it was considered as grade 1, provided they did not interfere with daily
activities. Those in grade 2 interfered with activities of daily living and grade 3 adverse events
prevented the daily living activities (Pepin et al., 2016).
Effect of the vaccine on the disease
The effect of the influenza vaccine on the disease was assessed by various randomised
control trials. With the vaccine administration the spread of infection was found to decrease.

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They study by Falsey et al. (2009) conducted a randomised controlled trials to determine the
safety of the intradermal (ID) trivalent influenza vaccine of high dose and compare with the
standard dose in older adults above 65 years of age. ID vaccines in older adults where more
immunogenic, then the SD vaccine. The HA titres were increased for both the A strains by the
influenza vaccine and was found slightly less for the B strain. In case of high dose older adult
recipients, post-vaccination seroconversion rates, geometric mean titers, and most seroprotection
rates were significantly higher when compared to standard dose recipients. Overall, both the ID
and the high dose vaccines were more immunogenic and tolerable in older adults. The results
with the young adults and older adults gave comparable results (Tsang et al. 2014).
Improvement in the vaccine
The currently available vaccines have several limitations. In addition, the compressed
production times and the complex manufacturing process trigger the need of new type of
vaccines. New types of vaccines are required to be formulated, which are more reliable,
effective, rapid and involves use advance production technology. In addition, to these properties,
the vaccines must be effective and safe to elicit antibodies. It will ensure licensing of the new
vaccines. The new vaccines are designed with the aim of increasing the surge capacity in the
pandemic situation. Thus, multiple approaches are under way to address these new demands.
The efficacy of the new vaccines must be correlated with the immune responses that are les
traditional including cellular responses, and antibodies against NA or M2 (Lambert & Fauci,
2010).
Recombinant proteins

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These proteins are in last stage of development. These are trivalent “HA protein–based
influenza vaccine”. The HA genes of Influenza are inserted in the bacculovirus and the vector is
infected to cell culture followed which the recombinant proteins are harvested and purified. This
vaccine will be effective against seasonal influenza (Soema et al., 2015).
Cold adapted influenza vaccine
This vaccine has protected millions of children in Russia. The licence for making such
vaccine in US has not been approved yet. These vaccines allows live virus to be administered
through nasal spray (containing isotonic solution of weakened virus particle). It is more
effective than the intradermal and intramuscular option. These vaccines were produced with
better cross-protective immunity. These vaccines trigger long lasting immunity. They induce
local neutralizing immunity and cell mediated immune responses. These vaccines have
massively reduced the secondary bacterial infections particularly for children upto 9 years of age
(Tlaxca et al., 2015).
Genetically engineered live influenza virus vaccines
This new vaccine approach uses technique of engineering to introduce sire directed
changes in the viral genome (negative-strand RNA) and other unique properties that are then
contained by vector (Si et al., 2016).
Live influenza virus vaccine candidates expressing altered NS1 genes
The influenza virus can be protected from the plasmid (vector) transfected cells. For
better stability, the insertions and deletions can be introduced in the genome to alter the NS1
gene to give protection against H5N1 and H9N2 avian influenza virus (Choi et al., 2015).

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Use of replication-defective influenza viruses as vaccine candidates
With the help of the biotechnology tools, it is easy to construct viral particles that
undergo single cycle of replications and can be inserted into appropriate vector. These candidates
of vaccine hold high potential of inducing long lasting antibody immune response. Cell mediate
immune response is stimulated without allowing the infectitious virus to replicate (Lee et al.,
2014).
Universal vaccines
Universal vaccines are enthusiastically developed with increasing optimism due to results
from the animal models. The purpose of formulating the universal vaccine is the goal of
stimulating the humoral and cellular responses in body similar to the natural infection. The
universal vaccines are intended to develop with the ability of long lasting and cross-strain
protection. The main target when developing universal vaccine is the conserved epitopes from
the influenza NP, HA proteins and matrix 1 (M1), and highly conserved external domain of the
influenza matrix 2 (M2) protein. The results from clinical testing showed that the vaccine when
administered alone or along with the carrier protein or adjuvant had effective outcomes. In
animal models two-step vaccination strategies have been used. The first dose comprise of DNA-
based HA vaccine priming and later second dose with an attenuated, inactivated, or adenovirus-
vector–based vaccine. The results showed release of cross-neutralizing antibodies. Although it
may not be possible to generate the true universal vaccine, efforts are made to consider some of
its properties (Lambert & Fauci, 2010).
DNA-based vaccines

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DNA vaccines were administered in animal models are. These vaccines are plasmid
DNA coated with influenza viral proteins. These vaccines showed promising results in animal
models and requires universal approach to make it effective for human use (Stachyra et al.,
2014).
Viral vectors
Viruses that cannot replicate or cause disease are used to deliver the viral protein of
influenza. The later are cloned into viruses like vaccinia, adenoviruses, and baculoviruses acting
as vector to contain vaccine. Results from trials show promising results in eliciting cellular and
antibody response ().
Virus like particles
Influenza vaccines can be developed from virus like particles that are non-infectious.
Cultured cell can be infected with the Recombinant viral vectors. These vectors may express HA,
M1 protein of influenza, and NA. These proteins can self assemble at plasma membrane. They
can bud from the infect cells as new virus that can enhance immune system (Soema et al., 2015).
New adjuvant approaches
Current vaccines are administered by intramuscular injections. Liposome like
preparations are been recently developed to improve the immunogenicity. The liposome vesicle
contains contain cholesterol and viral particles. When delivered subcutaneously or intranasally in
mice, showed effective results. However, there is a need of more accurate results to prove its
efficacy (Lee et al., 2014).

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Conclusion
In the field of vaccine development a significant improvement have been witnessed. New
vaccine technologies hold promising results and are anticipated to give enhanced protection.
These vaccines are on the process of development and can be used for human purpose after
approval. Efforts are made to reduce the mismatches between the vaccine strains and circulating
viruses. In order to make decision there is need of more clinical studies determining the efficacy
of the vaccine against placebo and standard vaccines.

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