Early in April 2009, several patients infected
with novel H1N1 swine-origin influenza virus A
(S-OIV A) were found in the United States and
Mexico. Through rapid and frequent international
travel, it has spread to over 74 countries around
the world and over 29,000 cases, including 145
deaths, have been reported up to June 12, 2009.1
On June 11, 2009, the World Health Organization
declared an influenza pandemic, caused by novel
S-OIV A (H1N1).
The three previous influenza pandemics,
A/H1N1 from 1918 to 1919, A/H2N2 from 1957
to 1963, and A/H3N2 from 1968 to 1970, were
characterized by a shift in the virus subtype, a shift
in the highest mortality to younger populations,
successive pandemic waves, higher transmissibility than seasonal influenza, and different impacts in different geographic regions.2The present novel H1N1 influenza has one of the most important characteristics, a shift in virus subtype, and it is very possible the other characteristics will develop.Clinical Manifestations According to a report of 642 confirmed cases of novel S-OIV A (H 1N1) infection in the United States, patients ranged from 3 months to 81 years in age; 60% of patients were ≤18 years, 40% were 10–18 years, and only 5% were ≥51 years.3There-fore, younger populations were much more susceptible than the elderly. The most common
©2009 Elsevier & Formosan Medical Association
........
(1)
Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University;2Research Center for Emerging Viral Infections, 3Department of Medical Biotechnology and Laboratory Science, and 4Clinical Virology Laboratory, Chang-Gung Memorial Hospital; 5Department of Pediatrics, Mackay Memorial Hospital;and 6Graduate Institute of Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.Received:June 5, 2009
Revised:June 13, 2009
Accepted:June 14, 2009*Correspondence to:Dr Li-Min Huang, Department of Pediatrics, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan.E-mail: lmhuang@ntu.edu.tw
†
Luan-Yin Chang and Shin-Ru Shih contributed equally to this work.
Novel Swine-origin Influenza Virus A (H1N1):The First Pandemic of the 21st Century
Luan-Yin Chang,1†Shin-Ru Shih,2,3,4†Pei-Lan Shao,1Daniel Tsung-Ning Huang,5Li-Min Huang 1,6*
An influenza epidemic was detected in April 2009 at the border between the United States and Mexico.The virus was identified soon after to be a swine-origin influenza virus A (S-OIV A) (H1N1). This virus has an HA gene that is derived from the 1918 swine influenza virus and other genes from human, avian, and Eurasian swine influenza viruses. Clinically, it behaves similarly to seasonal influenza. The only differen-tiating characteristics are vomiting and diarrhea in a quarter of infected patients, which are rare in sea-sonal influenza. On June 11, 2009, the World Health Organization declared the first pandemic of the 21st century, caused by S-OIV A (H1N1). Vaccination is the only way to dampen this pandemic. Many ques-tions await answers, including the clinical impact of the pandemic, optimal doses of vaccine, and the fu-ture destiny of the virus. A breakthrough in vaccinology against influenza is needed to address the recurring influenza pandemic. [J Formos Med Assoc 2009;108(7):526–532]
Key Words:influenza vaccine, influenza, pandemic, reassortment, swine influenza
presenting symptoms were fever (94%), cough (92%), and sore throat (66%); 25% of patients had diarrhea, and 25% had vomiting. Of the 399 patients for whom hospitalization status was known, 36 (9%) required hospitalization.3Of 22 hospitalized patients with available data, 12 had underlying characteristics that conferred an in-creased risk of severe seasonal influenza, and 11 had radiologically confirmed pneumonia. These included one (in each group) with pneumome-diastinum, necrotizing pneumonia, and empyema that was surgically drained (no microbiological growth was detected in the fluid). Eight patients required admission to an intensive care unit, and four had respiratory failure that required mechan-ical ventilation. A 22-month-old child with neona-tal myasthenia gravis and a 33-year-old pregnant woman have died.3
Therefore, most confirmed cases of novel S-OIV A (H1N1) infection have been character-ized by self-limited, uncomplicated febrile respi-ratory illness and symptoms similar to those of seasonal influenza (a cough, a sore throat, rhinor-rhea, headache, and myalgia). Approximately 38% of cases have also developed vomiting or diarrhea, neither of which is typical of seasonal influenza. Some patients have developed severe illness and required hospitalized, and two patients have died. The observation that 60% of patients were ≤18 years old suggests that children and young adults are more susceptible than older persons, or that because of differences in social networks, trans-mission to older persons has be
en delayed. It is also possible that elderly persons may have had some level of cross-protection from preexisting antibodies against other influenza A (H1N1) viruses—this requires further confirmation.
Is There Any Cross-protection of Seasonal Influenza Vaccine Against
the Novel S-OIV A (H1N1)?
The United States Centers for Disease Control (CDC) has assessed the level of cross-reactive an-tibody to the novel influenza A (H1N1) virus in cohorts of children and adults before and after vaccination with the 2005–2006, 2006–2007, 2007–2008, or 2008–2009 seasonal influenza vac-cines.4In children, before vaccination, there were no cross-reactive antibodies to S-OIV A (H1N1). Among adults, before vaccination, cross-reactive antibodies were detected in 6–9% of those aged 18–64 years, and in 33% of those aged >60 years. Previous vaccination of children with any of the four seasonal trivalent, inactivated influenza vaccines (TIVs), or with live attenuated influenza vaccine, did not elicit a cross-reactive antibody response to S-OIV A (H1N1).4In adults aged 18–64 years, vaccination with seasonal TIV re-sulted in a twofold increase in cross-reactive anti-body response to S-OIV A (H1N1), compared with a 12- to 19-fold increase in response to the sea-sonal H1N1 strain. No increase in cross-reactive antibody response to the S-OIV A (H1N1) was observed among adults aged
>60 years.4These data suggested that receipt of recent (2005–2009) seasonal influenza vaccines did not elicit a pro-tective antibody response to the novel influenza A (H1N1) virus. In addition, the researchers suggested that about one third of those aged >60 years may have had preexisting cross-reactive antibodies—this may explain why only 5% of S-OIVA (H1N1) patients were ≥51 years.3
Case–fatality Rate (CFR) and Reproduction Number (R0) of
the Novel H1N1 Influenza
By analyzing the outbreak in Mexico, early data on international spread, and viral genetic diver-sity, Fraser et al made an early assessment of trans-missibility and severity.5Their estimates suggested that 23,000 (range, 6000–32,000) of individuals were infected in Mexico by late April, which gave an estimated CFR of 0.4% (range, 0.3–1.5%), based on confirmed and suspect deaths reported by that time. In a community outbreak in the small community of La Gloria, Veracruz, no deaths were attributed to infection, which gave an upper
95% bound CFR of 0.6%. Thus, while substantial
uncertainty remains, clinical severity appears less than that seen in 1918 but comparable with that in 1957.
Clinical attack rate in children aged <15 years in La Gloria was 61%, which was more than twice that in adults aged ≥15 years (29%). R0 is defined as the average number of secondary cases gener-ated by a primary case. Three different epidemio-logical analyses estimated R0 to be 1.4–1.6, while a genetic analysis gave a central estimate of 1.2. This range of values was consistent with 14 to 73 generations of human-to-human transmission that occurred in Mexico by late April. Transmissi-bility was therefore substantially higher than for seasonal influenza, and comparable with lower estimates of R0 obtained from previous influenza pandemics.
Risk Factors for Severe Cases or Mortality
To date, there is insufficient information about the clinical complications of S-OIV A (H1N1) infection. Deaths have been caused by previous variants of swine influenza viruses and the novel H1N1 virus. While data are being collected on the spectrum of illnesses and complication risk asso-ciated with infection, clinicians should expect that both this and seasonal influenza infections will share the same age and risk factors.
Groups at higher risk of seasonal influenza complications include: children aged <5 years; persons aged ≥65 years; children and adolescents aged <18 years who are receiving long-term as-pirin therapy, and who might be at risk for Reye’s syndrome after influenza; pregnant women; adults and children who have chronic pulmonary, cardio-vascular, hepatic, hematological, neurological, neu-romuscular, or metabolic disorders; adults and children with immunosuppression caused by med-ication or human immunodeficiency virus; and residents of nursing homes and other chronic-care facilities.
The risk factors for complications of the pres-ent S-OIV A (H1N1) infection may be similar to those of seasonal influenza. H owever, the 1918 epidemic and the early reports of the pres-ent S-OIV A (H1N1) outbreak have shown that younger rather than older people are more sus-ceptible, and that infected patients of any age should be observed carefully for the occurrence of complications.
Transmission: Pandemic Threat and Infection Control
Pending clarification of transmission patterns for the S-OIV A (H1N1), the CDC recommends that personnel providing direct care for patients pre-senting with febrile respiratory illness (fever >37.8°C, plus one or more of the following: rhi-norrhea or nasal congestion, sore throat, cough), in a community
in which S-OIV A (H1N1) infec-tion has been reported, should wear a disposable N95 respirator, a gown, gloves, and goggles when entering the patient’s room. The patient should also wear a surgical mask and be placed in a pri-vate room, preferably an airborne infection iso-lation room. These are interim recommendations and subject to change at any time. H ealthcare personnel entering the room of a patient in iso-lation should be limited to those performing di-rect patient care. It is vital to promote good hand washing and respiratory/cough etiquette for the prevention of all respiratory infections in the healthcare setting.
Antiviral Therapy and Post-exposure Antiviral Chemoprophylaxis
Either oseltamivir or zanamivir is recommended for treatment of S-OIV A (H1N1) infection, in-cluding all hospitalized patients with confirmed, probable, or suspected novel infection, and symp-tomatic patients who are at higher risk of seasonal influenza complications. Post-exposure antiviral chemoprophylaxis with oseltamivir or zanamivir should be considered for the following: close con-
tacts of cases (confirmed, probable or suspected)
and healthcare personnel; public health workers; or those who have had recognized, unprotected, close-contact exposure to an infected person (con-firmed, probable or suspected) during that person’s infectious period.
Characteristics of Novel S-OIV A (H1N1)
in Humansreactive to
Where did the swine influenza virus
come from?
Influenza A virus can infect various host species, including birds, humans, and swine. Influenza A H1N1 virus was first isolated from swine in 19306and from humans in 1933.7Swine influ-enza A viruses are antigenically very similar to the 1918 human influenza A virus, and they may all have originated from a common ancestor.8,9From 1930 to the late 1990s, swine influenza A viruses were called “classical swine influenza” and they have remained relatively stable antigenically.10,11 In around 1998, the classical swine influenza virus resorted with human influenza A H3N2 virus and a North American Lineage avian influenza virus (unknown subtype), which resulted in the emergence of
a triple resorted H3N2 swine virus. This resorted virus has been circulating in the swine population throughout North America.12–14Also in around 1998, the triple resorted H3N2 virus resorted again with the classical swine influenza virus. This generated two new subtypes of swine influenza A virus, the H1N1 and the H1N2 viruses,11which have been circulating in the Asian swine population. Although human and swine H1N1 viruses are all of avian origin, they have evolved in different host species. Antigenic drift has occurred amongst different lineages of H1N1 viruses; therefore, cross-protection anti-bodies against avian, swine, and human H1N1 viruses are not expected to exist. Indeed, a recent study has demonstrated that ferret post-infection antisera raised against the currently circulating, seasonal human H1N1 viruses did not react with the novel S-OIV, according to a hemagglutination inhibition assay.15
The newly emerged S-OIV A (H1N1) contains a combination of gene segments that have not been previously identified in swine or human in-fluenza viruses. The PB2 and PA genes originated from an avian virus that was introduced into swine viruses around 1998. PB1 originated from the human H3N2 virus, which acquired the gene from an avian virus in 1968. HA, NP, and NS genes came from classical swine virus and these three genes are closely related to the 1918 human in-fluenza A virus. The other two genes, NA and M, were from the Eurasian swine virus and were in-troduced to swine viruses in 1979.16The Figure depicts the origins of each gene segment of S-OIV A (H1N1).
NA and M are the targets of two classes of clinically used antivirals, oseltamivir (Tamiflu)/ zanamivir (Relenza) and amantadine/rimantadine. Eurasian swine viruses are oseltamivir-sensitive and amantadine-resistant. The novel S-OIV A (H1N1) also has inherited sensitivity to oseltamivir and resistance to amantadine.16
Virulence factors of S-OIV A (H1N1)
The mortality rate for infection with S-OIV A (H1N1) appears not to be particularly high. However, virulence may change as the number of adaptive gene mutations increases, and the virus may have more opportunities to replicate in the new host species. Like other influenza A viruses, swine influenza virus enters host cells by binding to receptors that contain sialic acid. Swine are known to contain two types of receptors, 2,6-linked sialic acids that appear abundantly in the human respiratory tract, and 2,3-linked sialic acids that tend to be found in avian cells. The binding affinity of S-OIV A (H1N1) to different sialic acids is unclear. However, since the S-OIV A (H1N1) has been transmitted from human to human, this virus is expected to bind to human receptors. However, adaptive mutations may occur that promote the binding of S-OIV A (H1N1) to 2,6-linked sialic acids, if more humans become infected in the near future.
Adaptive mutations may occur in any other
gene segments apart from the receptor binding
site, and alter viral pathogenesis and virulence.
Currently, predicting which adaptive mutations
will increase or reduce the virulence of S-OIV A
(H1N1) is difficult. However, the following genetic
features may be of interest.
PB2 is a viral ribonucleoprotein subunit that
is responsible for viral replication in cells infected
with influenza virus, and is considered to be a
genetic factor that is associated with host restric-
tion. Almost all of the human influenza A viruses
have lysine (K) at position 627 in the PB2 pro-
tein, and most of the avian viruses have glutamic
acid (E) at this position.17The E to K mutation in
an avian virus has been shown to increase its vir-
ulence in mammalian experimental systems.18
The PB2 gene segment of S-OIV A (H1N1) has
resorted from an avian influenza A virus of an
unknown subtype and has retained E at position
627. H7N7 avian influenza viruses have infected
humans previously, and one human isolate from
a fatal case has been found to have the E to K
mutation.19Therefore, monitoring changes in the
amino acid sequence at position 627 of S-OIV
A (H1N1) in humans is important for predicting
a change in virulence.
PB1-F2 is translated from another reading frame of the PB1 gene segment because of an al-ternative translation initiation, and has also been reported to increase the pathogenicity of the 1918virus and the highly pathogenic H5N1 virus.18,20The PB1 gene of the novel S-OIV A (H1N1) has been found to have truncated forms of PB1-F2because of the presence of a stop codon at posi-tion 12. Hence, a point mutation at position 12may lead to production of a full-length PB1-F2in the novel S-OIV to increase viral pathogenicity in humans. However, the mutation may not be favored in human hosts because human viruses have tended not to express PB1-F2 as they have evolved in humans.21Another well-known virulence factor for the influenza virus is the NS1 protein. NS1 protein suppresses the antiviral mechanism in host cells upon viral infection.22The C-terminal domain of the N
S1 protein contains the ESEV signal in many avian influenza A viruses; this signal interacts with cellular modulators that contain the PDZ domain.This interaction may increase viral pathogenicity.Although the NS gene segment of S-OIV A (H1N1)
originated from an avian virus, it is truncated by 2009/A/H1N1
PB2, PA
Figure.The origin of each gene segment of swine-origin influenza virus A (H1N1). NA and M were derived from the Eurasian swine virus that originated from the Eurasian avian influenza A virus. The remaining genes were derived from the triple resorted swine virus that originated from different lineages of avian viruses.