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Senior Moderator
Implications of the Emergence of a Novel H1 Influenza Virus
Robert B. Belshe, M.D.
In this issue of the Journal, there are two reports
of recent transmissions of swine influenza viruses
in humans. One group of viruses, described by
Shinde et al.,1 are triple reassortants of viruses
from pigs, humans, and birds, called triple-reassortant
swine influenza A (H1) viruses, which
have circulated in pigs for more than a decade.
The other group, described by the Novel Swine-
Origin Influenza A (H1N1) Virus Investigation
Team,2 is a recent reassortant of the triple-reassortant
swine influenza A (H1) viruses and a
Eurasian swine influenza virus, resulting in the
swine-origin influenza A (H1N1) virus (S-OIV),
currently being transmitted among humans.
The two groups of viruses behave very differently.
Triple-reassortant swine influenza A (H1)
viruses are found in pigs and may occasionally be
transmitted to humans but have not spread efficiently
from human to human. S-OIV, in contrast,
is not currently known to be epidemic in
pigs (although pigs may be infected by exposure
to humans), but it is exhibiting human-to-human
transmission and has spread to several countries.
Both viruses are H1 hemagglutinin viruses, which
appeared in humans and swine in 1918 and have
subsequently evolved, in both species, into divergent
H1 viruses. The current situation is not ?1918
again,? it is ?1918 continued,? in that we are still
being infected with remnants of the 1918 pandemic
influenza virus.
Most adults have substantial immunity to H1
variants that have circulated among humans from
1918 through 1957 and then again from 1977
through the present. Whether cross-reacting antibodies
from previous H1 infections will provide
protection against S-OIV is not known, but
the epidemiologic features of the current S-OIV
infections suggest that there may be partial protection
from multiple previous influenza infections.
The age range of the 642 patients with confirmed
cases of S-OIV infection was 3 months to
81 years, but 60% were 18 years of age or younger.
This age distribution is typical for seasonal influenza;
schoolchildren are the group with the
highest rates of influenza, and they spread the
virus to household contacts.3 The clinical manifestations
of S-OIV also were typical of seasonal
influenza, with fever in 94% of patients, cough in
92%, and sore throat in 66%; in addition, however,
vomiting (found in 25%) or diarrhea (found
in 25%) was common. A total of 36 patients were
hospitalized; of the 22 hospitalized patients for
whom data were available, several had risk factors:
young age (4 patients) or chronic medical conditions
(9 patients) or both, or pregnancy (1 patient).
The two deaths occurred in a 22-month-old
child with chronic medical conditions and a 33-
year-old woman who was pregnant. Several hospitalized
patients had evidence of pneumonia on
radiography, and some had secondary complications.
The spectrum of illnesses seems very much
like those of seasonal influenza.
Many questions remain. Will S-OIV virus replace
the human H1 virus as the seasonal influenza
virus and evolve antigenic variants every year?
Will the virus reassort with H3 influenza virus to
make yet another variant? Will S-OIV further adapt
to humans and become more severe, causing a
wave of influenza in the fall season with higher
mortality? When will a vaccine be available?
The U.S. government contributed financial assistance
to influenza-vaccine manufacturers to expand
domestic capacity to produce vaccine4; although
expansion plans are still ongoing, now is
the time for those manufacturers to deliver. Completing
seasonal-vaccine production and adding a
monovalent S-OIV vaccine to production will be
challenging both technically and in terms of pol-
icy, but it can be done. The development of highgrowth
seed viruses for the production of inactivated
vaccine is needed, as is the creation of
reassortants of S-OIV with a live-attenuated ?backbone?
virus for the manufacture of intranasal vaccine.
Pilot lots of vaccine need to be produced
quickly for testing through clinical trials to determine
the safety, the dose, and the number of doses
needed.
Dose?response and small safety studies should
be carried out over the summer months. Many
will recall 1976, when an H1 influenza virus of
swine origin infected soldiers at Fort Dix, New
Jersey, and one soldier died.5 The concern then
was that a new pandemic was brewing; a vaccine
was developed over the summer months, with
clinical trials used to determine the amount and
number of doses. Two doses of the vaccine were
necessary for persons under the age of 25 years,
but older persons had been primed, through natural
infection with viruses circulating in the previous
H1 era (1918 through 1957) and needed only
a single dose to stimulate antibodies against the
virus.5 The government recommended nationwide
vaccination, which was performed in more
than 40 million people; unexpectedly, Guillain?
Barr? syndrome developed in approximately 1 in
100,000 vaccinated persons ? a rate 5 to 10 times
the background rate.6,7 The cause is believed to
have been cross-reacting antibodies against peripheral-
nerve antigen that may develop after vaccination
with the H1 influenza virus of swine
origin.8 The virus did not reappear, and vaccinations
were halted. Whether the S-OIV antigen will
cause adverse events if used in a vaccine is not
known. Difficult policy decisions loom, but the
pathway to a vaccine is clear, and production needs
to proceed apace. The spread of the current S-OIV
is far beyond that of the 1976 event.
The emergence and spread of S-OIV brings
out the best and worst of contemporary society.
Within days after the first case identification of
S-OIV infection in the United States, the scientific
community had the complete genetic sequence of
the hemagglutinin, and Internet dissemination
of the information made it available to everyone
for further analysis. Public health and surveillance
activities were heightened. Drug susceptibility was
determined: S-OIV is susceptible to oseltamivir
and zanamivir but resistant to amantadine and
rimantadine.
In contrast, inflammatory political posturing
has occurred that illustrates the need for effective
communication by physicians and scientists
to the public. Some have asked, Why didn?t you
close the borders? (Answer: It doesn?t work.) Misguided
culling of pigs has also been carried out
in one country, but S-OIV is not epidemic in pigs;
people are spreading the virus.
Finally, funding for surveillance, public health
efforts, and vaccine development needs to be enhanced.
The current S-OIV epidemic is only the
latest influenza virus, not the last.
Dr. Belshe reports serving as a consultant or speaker for
MedImmune and Novartis. No other potential conflict of interest
relevant to this article was reported.
From the Division of Infectious Diseases and Immunology,
Saint Louis University, St. Louis.
This article (10.1056/NEJMe0903995) was published at NEJM.
org on May 7, 2009.
1. Shinde V, Bridges CB, Uyeki TM, et al. Triple-reassortant swine
influenza A (H1) in humans in the United States, 2005?2009.
N Engl J Med 2009;361. DOI: 10.1056/NEJMoa0903812.
2. Novel Swine-Origin Influenza A (H1N1) Virus Investigation
Team. Emergence of a novel swine-origin influenza A
(H1N1) virus in humans. N Engl J Med 2009;361. DOI: 10.1056/
NEJMoa0903810.
3. Glezen WP, Taber LH, Frank AL, Gruber WC, Piedra PA. Influenza
virus infections in infants. Pediatr Infect Dis J 1997;
16:1065-8.
4. Basu S. Administration awards flu vaccine funding for new
manufacturing methods. U.S. Medicine. June 2006. (Accessed
May 6, 2009, at http://www.usmedicine.com/article.cfm?articleID=
1321&issueID=88.)
5. Sencer DJ, Millar JD. Reflections on the 1976 swine flu vaccination
program. Emerg Infect Dis 2006;12:29-33.
6. Marks JS, Halpin TJ. Guillain-Barr? syndrome in recipients
of A/New Jersey influenza vaccine. JAMA 1980;243:2490-4.
7. Schonberger LB, Bregman DJ, Sullivan-Bolyai JZ, et al. Guillain-
Barr? syndrome following vaccination in the National Influenza
Immunization Program, United States, 1976?1977. Am J
Epidemiol 1979;110:105-23.
8. Nachamkin I, Shadomy SV, Moran AP, et al. Anti-ganglioside
antibody induction by swine (A/NJ/1976/H1N1) and other influenza
vaccines: insights into vaccine-associated Guillain-Barr?
syndrome. J Infect Dis 2008;198:226-33.
Copyright ? 2009 Massachusetts Medical Society.
Copyright ? 2009 Massachusetts Medical Society. All rights reserved.
Downloaded from www.nejm.org on May 8, 2009 . For personal use only. No other uses without permission
Robert B. Belshe, M.D.
In this issue of the Journal, there are two reports
of recent transmissions of swine influenza viruses
in humans. One group of viruses, described by
Shinde et al.,1 are triple reassortants of viruses
from pigs, humans, and birds, called triple-reassortant
swine influenza A (H1) viruses, which
have circulated in pigs for more than a decade.
The other group, described by the Novel Swine-
Origin Influenza A (H1N1) Virus Investigation
Team,2 is a recent reassortant of the triple-reassortant
swine influenza A (H1) viruses and a
Eurasian swine influenza virus, resulting in the
swine-origin influenza A (H1N1) virus (S-OIV),
currently being transmitted among humans.
The two groups of viruses behave very differently.
Triple-reassortant swine influenza A (H1)
viruses are found in pigs and may occasionally be
transmitted to humans but have not spread efficiently
from human to human. S-OIV, in contrast,
is not currently known to be epidemic in
pigs (although pigs may be infected by exposure
to humans), but it is exhibiting human-to-human
transmission and has spread to several countries.
Both viruses are H1 hemagglutinin viruses, which
appeared in humans and swine in 1918 and have
subsequently evolved, in both species, into divergent
H1 viruses. The current situation is not ?1918
again,? it is ?1918 continued,? in that we are still
being infected with remnants of the 1918 pandemic
influenza virus.
Most adults have substantial immunity to H1
variants that have circulated among humans from
1918 through 1957 and then again from 1977
through the present. Whether cross-reacting antibodies
from previous H1 infections will provide
protection against S-OIV is not known, but
the epidemiologic features of the current S-OIV
infections suggest that there may be partial protection
from multiple previous influenza infections.
The age range of the 642 patients with confirmed
cases of S-OIV infection was 3 months to
81 years, but 60% were 18 years of age or younger.
This age distribution is typical for seasonal influenza;
schoolchildren are the group with the
highest rates of influenza, and they spread the
virus to household contacts.3 The clinical manifestations
of S-OIV also were typical of seasonal
influenza, with fever in 94% of patients, cough in
92%, and sore throat in 66%; in addition, however,
vomiting (found in 25%) or diarrhea (found
in 25%) was common. A total of 36 patients were
hospitalized; of the 22 hospitalized patients for
whom data were available, several had risk factors:
young age (4 patients) or chronic medical conditions
(9 patients) or both, or pregnancy (1 patient).
The two deaths occurred in a 22-month-old
child with chronic medical conditions and a 33-
year-old woman who was pregnant. Several hospitalized
patients had evidence of pneumonia on
radiography, and some had secondary complications.
The spectrum of illnesses seems very much
like those of seasonal influenza.
Many questions remain. Will S-OIV virus replace
the human H1 virus as the seasonal influenza
virus and evolve antigenic variants every year?
Will the virus reassort with H3 influenza virus to
make yet another variant? Will S-OIV further adapt
to humans and become more severe, causing a
wave of influenza in the fall season with higher
mortality? When will a vaccine be available?
The U.S. government contributed financial assistance
to influenza-vaccine manufacturers to expand
domestic capacity to produce vaccine4; although
expansion plans are still ongoing, now is
the time for those manufacturers to deliver. Completing
seasonal-vaccine production and adding a
monovalent S-OIV vaccine to production will be
challenging both technically and in terms of pol-
icy, but it can be done. The development of highgrowth
seed viruses for the production of inactivated
vaccine is needed, as is the creation of
reassortants of S-OIV with a live-attenuated ?backbone?
virus for the manufacture of intranasal vaccine.
Pilot lots of vaccine need to be produced
quickly for testing through clinical trials to determine
the safety, the dose, and the number of doses
needed.
Dose?response and small safety studies should
be carried out over the summer months. Many
will recall 1976, when an H1 influenza virus of
swine origin infected soldiers at Fort Dix, New
Jersey, and one soldier died.5 The concern then
was that a new pandemic was brewing; a vaccine
was developed over the summer months, with
clinical trials used to determine the amount and
number of doses. Two doses of the vaccine were
necessary for persons under the age of 25 years,
but older persons had been primed, through natural
infection with viruses circulating in the previous
H1 era (1918 through 1957) and needed only
a single dose to stimulate antibodies against the
virus.5 The government recommended nationwide
vaccination, which was performed in more
than 40 million people; unexpectedly, Guillain?
Barr? syndrome developed in approximately 1 in
100,000 vaccinated persons ? a rate 5 to 10 times
the background rate.6,7 The cause is believed to
have been cross-reacting antibodies against peripheral-
nerve antigen that may develop after vaccination
with the H1 influenza virus of swine
origin.8 The virus did not reappear, and vaccinations
were halted. Whether the S-OIV antigen will
cause adverse events if used in a vaccine is not
known. Difficult policy decisions loom, but the
pathway to a vaccine is clear, and production needs
to proceed apace. The spread of the current S-OIV
is far beyond that of the 1976 event.
The emergence and spread of S-OIV brings
out the best and worst of contemporary society.
Within days after the first case identification of
S-OIV infection in the United States, the scientific
community had the complete genetic sequence of
the hemagglutinin, and Internet dissemination
of the information made it available to everyone
for further analysis. Public health and surveillance
activities were heightened. Drug susceptibility was
determined: S-OIV is susceptible to oseltamivir
and zanamivir but resistant to amantadine and
rimantadine.
In contrast, inflammatory political posturing
has occurred that illustrates the need for effective
communication by physicians and scientists
to the public. Some have asked, Why didn?t you
close the borders? (Answer: It doesn?t work.) Misguided
culling of pigs has also been carried out
in one country, but S-OIV is not epidemic in pigs;
people are spreading the virus.
Finally, funding for surveillance, public health
efforts, and vaccine development needs to be enhanced.
The current S-OIV epidemic is only the
latest influenza virus, not the last.
Dr. Belshe reports serving as a consultant or speaker for
MedImmune and Novartis. No other potential conflict of interest
relevant to this article was reported.
From the Division of Infectious Diseases and Immunology,
Saint Louis University, St. Louis.
This article (10.1056/NEJMe0903995) was published at NEJM.
org on May 7, 2009.
1. Shinde V, Bridges CB, Uyeki TM, et al. Triple-reassortant swine
influenza A (H1) in humans in the United States, 2005?2009.
N Engl J Med 2009;361. DOI: 10.1056/NEJMoa0903812.
2. Novel Swine-Origin Influenza A (H1N1) Virus Investigation
Team. Emergence of a novel swine-origin influenza A
(H1N1) virus in humans. N Engl J Med 2009;361. DOI: 10.1056/
NEJMoa0903810.
3. Glezen WP, Taber LH, Frank AL, Gruber WC, Piedra PA. Influenza
virus infections in infants. Pediatr Infect Dis J 1997;
16:1065-8.
4. Basu S. Administration awards flu vaccine funding for new
manufacturing methods. U.S. Medicine. June 2006. (Accessed
May 6, 2009, at http://www.usmedicine.com/article.cfm?articleID=
1321&issueID=88.)
5. Sencer DJ, Millar JD. Reflections on the 1976 swine flu vaccination
program. Emerg Infect Dis 2006;12:29-33.
6. Marks JS, Halpin TJ. Guillain-Barr? syndrome in recipients
of A/New Jersey influenza vaccine. JAMA 1980;243:2490-4.
7. Schonberger LB, Bregman DJ, Sullivan-Bolyai JZ, et al. Guillain-
Barr? syndrome following vaccination in the National Influenza
Immunization Program, United States, 1976?1977. Am J
Epidemiol 1979;110:105-23.
8. Nachamkin I, Shadomy SV, Moran AP, et al. Anti-ganglioside
antibody induction by swine (A/NJ/1976/H1N1) and other influenza
vaccines: insights into vaccine-associated Guillain-Barr?
syndrome. J Infect Dis 2008;198:226-33.
Copyright ? 2009 Massachusetts Medical Society.
Copyright ? 2009 Massachusetts Medical Society. All rights reserved.
Downloaded from www.nejm.org on May 8, 2009 . For personal use only. No other uses without permission