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A Recombinant Viruslike Particle Influenza A (H7N9) Vaccine
November 13, 2013DOI: 10.1056/NEJMc1313186
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To the Editor:
Avian-origin influenza A (H7N9) viruses emerged as human pathogens in China in 2013 and have caused 137 cases and 45 deaths to date.1 These viruses have acquired mutations that could facilitate infection in mammals,2 which could pose a pandemic threat if the viruses become readily transmissible in humans. Vaccines are a key defense against pandemics, but candidate vaccines featuring H7 hemagglutinins (HA) have been poorly immunogenic.3
We have previously described the development, manufacture, and efficacy in mice of an A/Anhui/1/13 (H7N9) viruslike particle (VLP) vaccine produced in insect cells with the use of recombinant baculovirus. This vaccine combines the HA and neuraminidase (NA) of A/Anhui/1/13 with the matrix 1 protein (M1) of A/Indonesia/5/05.4,5
We enrolled 284 adults (≥18 years of age) in a randomized, observer-blinded, placebo-controlled clinical trial of this vaccine; all the participants provided written informed consent. The trial was approved by the Bellberry Human Research Ethics Committee in Adelaide, Australia (ClinicalTrials.gov number, NCT01897701). (Additional details are provided in the study protocol, available with the full text of this letter at NEJM.org.) Study participants received two identical doses, 21 days apart, of placebo, vaccine alone at doses delivering 15 μg or 45 μg of HA, or vaccine at doses delivering 5 μg or 15 μg of HA combined with 30 or 60 units of the saponin-based ISCOMATRIX adjuvant. A total of 37 participants (13%) were excluded from the per-protocol analysis before unblinding because of protocol violations.
The VLP vaccine with adjuvant was associated with increased local and systemic reactions. Few of these reactions were severe, and no body temperatures exceeded 38.5?C. The sole serious adverse event was a recurrence of a previous illness (for details, see the Supplementary Appendix, available at NEJM.org). By day 35, after immunizations at day 0 and day 21, seroconversion and hemagglutination-inhibition (HAI) reciprocal antibody titers of 40 or more (the value cited by regulatory authorities as having a potential association with clinical benefit) were detected in 5.7% and 15.6% of participants receiving 15 μg and 45 μg of HA, respectively, without adjuvant. In contrast, three of the four treatment groups receiving VLPs with adjuvant had HAI seroconversion and reciprocal titers of 40 or more in more than 60% of participants, including 80.6% of those receiving 5 μg of HA with 60 units of adjuvant (Table 1Table 1Summary of A/Anhui/1/13 Antibody Responses in the Per-Protocol Population.). Significant increases in N9 neuraminidase-inhibiting antibodies occurred in up to 71.9% of recipients of the vaccine without adjuvant, 92.0% of recipients of vaccine with 30 units of adjuvant, and 97.2% of recipients of vaccine with 60 units of adjuvant (Table 1). The vaccines that were studied here were release for human use within 3 months after the availability of the HA and NA sequences.4,5
November 13, 2013DOI: 10.1056/NEJMc1313186
Share:
Article
To the Editor:
Avian-origin influenza A (H7N9) viruses emerged as human pathogens in China in 2013 and have caused 137 cases and 45 deaths to date.1 These viruses have acquired mutations that could facilitate infection in mammals,2 which could pose a pandemic threat if the viruses become readily transmissible in humans. Vaccines are a key defense against pandemics, but candidate vaccines featuring H7 hemagglutinins (HA) have been poorly immunogenic.3
We have previously described the development, manufacture, and efficacy in mice of an A/Anhui/1/13 (H7N9) viruslike particle (VLP) vaccine produced in insect cells with the use of recombinant baculovirus. This vaccine combines the HA and neuraminidase (NA) of A/Anhui/1/13 with the matrix 1 protein (M1) of A/Indonesia/5/05.4,5
We enrolled 284 adults (≥18 years of age) in a randomized, observer-blinded, placebo-controlled clinical trial of this vaccine; all the participants provided written informed consent. The trial was approved by the Bellberry Human Research Ethics Committee in Adelaide, Australia (ClinicalTrials.gov number, NCT01897701). (Additional details are provided in the study protocol, available with the full text of this letter at NEJM.org.) Study participants received two identical doses, 21 days apart, of placebo, vaccine alone at doses delivering 15 μg or 45 μg of HA, or vaccine at doses delivering 5 μg or 15 μg of HA combined with 30 or 60 units of the saponin-based ISCOMATRIX adjuvant. A total of 37 participants (13%) were excluded from the per-protocol analysis before unblinding because of protocol violations.
The VLP vaccine with adjuvant was associated with increased local and systemic reactions. Few of these reactions were severe, and no body temperatures exceeded 38.5?C. The sole serious adverse event was a recurrence of a previous illness (for details, see the Supplementary Appendix, available at NEJM.org). By day 35, after immunizations at day 0 and day 21, seroconversion and hemagglutination-inhibition (HAI) reciprocal antibody titers of 40 or more (the value cited by regulatory authorities as having a potential association with clinical benefit) were detected in 5.7% and 15.6% of participants receiving 15 μg and 45 μg of HA, respectively, without adjuvant. In contrast, three of the four treatment groups receiving VLPs with adjuvant had HAI seroconversion and reciprocal titers of 40 or more in more than 60% of participants, including 80.6% of those receiving 5 μg of HA with 60 units of adjuvant (Table 1Table 1Summary of A/Anhui/1/13 Antibody Responses in the Per-Protocol Population.). Significant increases in N9 neuraminidase-inhibiting antibodies occurred in up to 71.9% of recipients of the vaccine without adjuvant, 92.0% of recipients of vaccine with 30 units of adjuvant, and 97.2% of recipients of vaccine with 60 units of adjuvant (Table 1). The vaccines that were studied here were release for human use within 3 months after the availability of the HA and NA sequences.4,5
