Influenza AH1N2 Viruses, United Kingdom, 2001-02 Influenza Season

Joanna S. Ellis, Adriana Alvarez-Aguero, Vicky Gregory, Yi Pu Lin, A. Hay, Maria C. Zambon


Emerging Infectious Diseases. 2003;9(2) 

In This Article


During the period September 2001-March 2002, clinical death indices for the measurement of influenzalike illness in England and Wales did not rise above baseline levels, indicating low influenza activity (Figure 1). Very low levels of influenza activity were also recorded in Scotland (data not shown). The clinical indices of influenzalike illness activity peaked in week 6 and correlated well with the peak of influenza viruses detected and typed by Central Public Health Laboratory (data not shown; available from: URL:

Consultation rate (per 100,000 population) for influenzalike illnesses with sentinel physicians in England in 1988-2002.

In September 2001, the first isolate of the influenza season (A/Scotland/122/2001), an H1N2 virus, was isolated from a 1-year-old child. H1N2 viruses continued to be isolated from the patients in the community and in hospitalized patients throughout the U.K. until the end of March 2002. H1N2 reassortant viruses co-circulated with a relatively equal proportion of H3N2 viruses throughout the season and a small number of H1N1 viruses. Of 420 influenza A viruses isolated and characterized in the winter of 2001-02, 54.0% were influenza A H1N2, 45.2% H3N2, and 0.7% A H1N1 subtype.

During the previous influenza season (2000-01), H1N1 and influenza B viruses co-circulated in the U.K., and no H3N2 viruses were detected. In comparison, only a small number of influenza B viruses were isolated during the winter of 2001-02 (data not shown; available from: URL:

Retrospective analysis using RT-PCR to determine the NA subtype, on 198 of 323 influenza A H1 viruses isolated during 2000-01, identified only a single H1N2 subtype virus isolated from a 9-year-old child in March 2001. Therefore, before September 2001, H1N2 viruses were not widely circulating in the U.K.

Despite the fact that H1N2 viruses emerged and were as frequently isolated as H3N2 viruses during the winter of 2001-02 in England, the levels of clinical influenzalike illness activity were among the lowest in the last 15 years (Figure 1). This low level indicates that the new H1N2 strain was not associated with particularly severe influenzalike illness activity. The low levels of influenzalike illness activity were also associated with correspondingly low levels of excess death rates (death from all causes), (available from: URL: More than 75% of H1N2 virus isolates were obtained from children <15 years of age (Figure 2), indicating that the major age group affected by the H1N2 viruses was young persons, possibly undergoing a primary infection. A similar proportion of H3N2 viruses isolated were also from children <15 years of age. Few H1N2 virus isolates were obtained from adults, and only a limited number were obtained from adults >65 years old. These facts suggest that the young are most susceptible to H1N2; adults and vaccinated elderly appear to have adequate protective immunity to the new subtype. Age-specific consultation data for influenzalike illness in 2001-02 confirm that the age range most severely affected by influenzalike illness was the 5-14 age group (data not shown; available from: URL:

Age distribution of patients from whom influenza A viruses isolated during 2001-02 in the U.K.

Antigenic characterization of the 228 H1N2 viruses isolated during 2001-02 was performed by using hemagglutination inhibition tests with postinfection ferret antisera to influenza A H1N1 and H3N2 reference and vaccine strains ( Table 2 ). The HA gene of the H1N2 viruses was antigenically related to that of the H1N1 strain used in vaccines in 2001-02, A/NewCaledonia/20/99, and was antigenically indistinguishable from that of co-circulating A/NewCaledonia/20/99-like H1N1 viruses. No significant indication of antigenic drift in the HA genes of these viruses was observed over the period the viruses were isolated (March 2001-March 2002) ( Table 2 ).

Phylogenetic analysis indicated that the HA1 sequences of the H1N2 viruses analyzed ( Table 1 ) were most closely related (sequence similarity of 98.7% to 99.1%) to those of the H1N1 vaccine strain, A/NewCaledonia/20/99 (Figure 3). The HA1 sequences of the H1N2 viruses analyzed were very similar, exhibiting only 0%-1.2% nucleotide divergence between sequences. This divergence is in contrast to that of A/NewCaledonia/20/99-like H1N1 viruses isolated in the U.K. during 2000-01, which exhibited 0.3%-3.1% nucleotide divergence in the HA1.

Phylogenetic tree of influenza A H1N1 and H1N2 virus HA1 nucleotide sequences.

Of the four amino acid differences previously observed in the HA1 sequences of H1N2 viruses isolated from various countries and compared to A/NewCaledonia/20/99,[23] all U.K. H1N2 viruses analyzed had the substitutions V169A and A193T. All but the earliest U.K. H1N2 viruses had the substitutions V178I and A218T in the HA1.

The NA genes of six H1N2 viruses analyzed ( Table 1 ) were closely related genetically to the NA genes of recently circulating H3N2 viruses, represented by A/Moscow/10/99 (99.1% nucleotide sequence homology). All analyzed H1N2 NA gene sequences from the U.K. differed from those of A/Moscow/10/99 at the three amino acid positions observed in the NA of H1N2 viruses isolated from other parts of the world.[23] In addition, with the exception of the earliest U.K. H1N2 isolate (A/England/627/2001), all analyzed H1N2 NA sequences from the U.K. had the substitution M24T, which is located in the transmembrane region of the protein.[25]

We observed no mutations in the NA or HA genes that have been reported to confer resistance to NA inhibitors.[26,27] None of the amino acid substitutions in the HA or NA genes resulted in the loss or creation of potential glycosylation sites in the HA or NA surface proteins of the H1N2 viruses.

A region of the M1 gene of nine H1N2 isolates ( Table 1 ) was analyzed and compared with sequences of prototype H1N1, H2N2, and H3N2 viruses, in addition to M1 gene sequence data obtained from influenza viruses isolated in the U.K. since 1951. Little sequence divergence was observed between the M1 sequences of the H1N2 viruses (0% to 0.9%), and they were most closely related to those of recent H3N2 viruses. No amino acid differences were seen between the partial M1 sequences of H1N2 viruses and those of A/Panama/2007/99, whereas one amino acid difference (R174K) was found from the M1 of A/Moscow/10/99. This substitution was first observed in H3N2 strains isolated in England in 1996 and was fixed in H3N2 viruses isolated after 1998 in the U.K.

Partial gene sequencing of the PB2, PB1, PA, NP, and NS genes indicated that the analyzed H1N2 viruses ( Table 1 ) also derived each of these genes from a virus of the H3N2 subtype. Very little sequence divergence was observed in these five genes of the H1N2 viruses analyzed.

The susceptibility of H1N2 virus replication to inhibition by amantadine was determined. All of the analyzed H1N2 viruses (A/Scotland/122/2001, A/England/45/2002, and A/England/63/2002) were susceptible to inhibition of virus growth by amantadine, with MIC 50 <0.1µg/mL of drug.