spread of the virus in host cells [11]. M2, present in minor quantities on the

membrane, is an ion channel that has an important role in early phases of the

infection. Inside the virus, each RNA segment is wrapped around nucleoprotein

(NP) monomers, forming viral ribonucleoprotein (RNP) complexes alongside with

the viral polymerases PB1, PB2 and PA. Attached to the inside of the membrane,

M1 (matrix) protein interacts with RNP complexes [8].

As mentioned before, IAVs and IBVs are responsible for influenza outbreaks

around the world. While both viruses result in similar burdens on public health for

seasonal epidemics [12], IAVs are also responsible for sporadic global pandemics

due to their greater genetic diversity and host range (infecting domestic animals,

pigs, poultry, and wild birds, while IBVs infect almost exclusively humans): all

known influenza pandemics were caused by IAVs, usually from zoonotic origin [4].

To this date, 18 HA and 11 NA subtypes were identified for IAVs, while only two

antigenic lineages are reported for IBVs. HA plays a critical role in species re-

striction: human influenza viruses have HAs specific to α2–6 terminal sialic acid

(SA) while avian HAs bind to α2–3 SA [2]. Influenza viruses undergo frequent

mutations as viral polymerase lacks proofreading activity, around one introduced

error per replicated genome [13]. When these mutations occur in the antigenic

portions of the HA and NA surface proteins, it may result in advantages that allow

some strains to escape pre-existing immunity, a process called antigenic drift.

Additionally, as the influenza genome is composed of discrete segments, coinfec-

tion of a same host cell with two different viruses may result in virions that contain

genome segments from both parental strains. This process, named antigenic shift, is

critical in pandemic formation as one single event is able to result in significant

antigenic modifications that allows, for example, the virus to jump from one species

to another eventually infecting humans [7]. A pandemic occurs when a new in-

fluenza strain, containing antigens that are significantly different from previous

viruses and to which humans have no or little immunity, appears and spreads, being

able to contaminate a significant percentage of the population [2,4].

9.3

THE ANNUAL CYCLE FOR INFLUENZA VACCINE

MANUFACTURING

Due to the high mutation rate of influenza viruses, a continuous surveillance of

worldwide influenza activity must be conducted in order to assure a good match

between seasonal vaccines and circulating strains, as well as to increase pre-

paredness for future pandemics. The Global Influenza Surveillance and Response

System (GISRS), coordinated by the World Health Organization since 1952, is

responsible for monitoring, isolation, and identification of influenza viruses causing

localized epidemics throughout the year. Samples from influenza patients collected

from around the world are sent to one of the more than 150 National Influenza

Centers for strain isolation and identification. Once a new strain is detected, it is

sent to one of the WHO’s reference laboratories for further antigenic and molecular

analysis. Twice a year, the WHO will carefully review the data generated and

announce the four influenza strains that are likely to circulate in the next flu season

for Northern and Southern Hemispheres [14]. From the time of this announcement,

Manufacturing of influenza vaccines

227