Expanding the Options for Confronting Pandemic Influenza

The majority of physicians and public health practitioners are familiar with the concept that the vast reservoir of influenza A viruses found in migratory waterfowl represent an ongoing threat to emerge in humans and cause widespread disease. Although these avian influenza A viruses, which include all of the known hemagglutinin (H1-H16) and neuraminidase (N1-N9) subtypes, are generally restricted in their ability to replicate in humans, recent work has shown that a minimal number of mutations can result in viruses likely to transmit efficiently from person to person.1,2 The resulting global epidemic or pandemic of influenza would spread rapidly and almost certainly would have massive public health implications. Among the many hemagglutinin subtypes, viruses of the H5 and more recently H7 subtypes are of particular concern because of their demonstrated ability to cause severe disease in humans.3,4 Vaccination will be a critical component of the strategy to mitigate the effects of such a pandemic, yet the successful development of such vaccines faces multiple formidable obstacles. The most straightforward strategy for pandemic vaccination would use approaches similar to those widely used for seasonal influenza vaccination. Initial studies of H5 vaccines demonstrated that much higher doses of vaccine would be needed than are used for seasonal influenza, and that at least 2 doses would be required for effective vaccination.5-7 The addition of oil-in-water emulsions, such as AS03 or MF59, substantially enhances the immunogenicity of H5N1 vaccines, allowing relatively small doses of vaccine to effectively induce antibody.5,8,9 However, even with adjuvants, a multiple dose schedule would still be needed, with obvious limitations in the face of a rapidly spreading pandemic. In this issue of JAMA, 2 reports10,11 provide important information that expands the available options for confronting pandemic influenza, and may help surmount those obstacles. In the report by Mulligan and colleagues,10 similar findings as previously reported for H5 viruses have now been extended to a candidate vaccine for the emerging H7N9 virus. In this randomized clinical trial, 700 adults aged 19-64 years received influenza A/Shanghai/2/13 (H7N9) inactivated virus vaccine intramuscularly on days 0 and 21 at nominal doses of 3.75 μg, 7.5 μg, 15 μg, or 45 μg of hemagglutinin with or without the adjuvant MF59. As expected, inactivated vaccines without adjuvant, even when given at relatively high doses, were not particularly immunogenic. When the oil-in-water adjuvant MF59 was added to the vaccine, hemagglutinin inhibition responses were generated in about half of recipients after 2 doses, even with doses of vaccine as low as 3.75 μg. However, a 2-dose schedule was needed to generate significant immune responses even with the use of the MF59 adjuvant. In considering the effect of the adjuvant, the investigators also evaluated whether adjuvant was needed for both doses, and found that if the supply of adjuvant were an issue, a reasonable approach would be to use the adjuvant for the first dose only. An additional challenge confronting pandemic vaccination is the ongoing evolution of antigenic variation among the potential threat viruses. The study by Belshe and colleagues11 extends previous studies of H5N1 vaccines and evaluates the potential to generate cross-protective responses, testing the ability of an A/Anhui/05 (genetic clade 2.3) vaccine to induce antibody against both this H5 influenza virus and the A/Vietnam/04 virus (clade 1). Similar to previous studies, the A/Anhui/05 vaccine was not very immunogenic in vaccine-naive individuals (n = 565), even with 2 doses of 90 μg. Adding the MF59 adjuvant substantially improved the response, so that doses as low at 3.75 μg were effective, even though a 2-dose schedule was still needed. However, cross-reactive responses were generally not seen in vaccine-naive study participants even with the addition of the adjuvant. Because of the enormous logistical difficulties of a 2-dose emergency vaccination program in the face of an emerging pandemic, there has also been interest in determining whether persons could be immunologically primed prior to a pandemic for vigorous immune responses to a single dose of vaccine at some point in the future. In this kind of strategy, populations would undergo prepandemic vaccination with representative examples of potential pandemic threat subtypes, such as H5 or H7, and then be immunized with a vaccine representing the emerging virus at the time a pandemic appears imminent. Several studies have shown that healthy adults who have received 2 doses of H5 vaccine can have extremely vigorous responses to a single dose of vaccine received many years later, even if the subsequent vaccine is antigenically variant from the vaccine used for the priming vaccinination.12,13 The study by Belshe et al11 extends these observations by including participants (n = 72) who had previously received a high dose (90 μg) of unadjuvanted A/Vietnam/04 vaccine and were subsequently randomized 1 year later to receive a low dose (3.75 μg) of A/Anhui/05 vaccine with or without MF59. In contrast to the results in vaccine-naive individuals, good responses were seen in previously vaccinated persons after a single dose, and reacted with both the Related articles pages 1420 and 1409 Opinion