All registered pandemic H1N1 vaccines were evaluated for safety and immunogenicity in clinical trials and met criteria required for licensure of seasonal influenza vaccines by regulatory authorities, including the Committee for Medicinal Products for Human Use (CHMP) in Europe and the Food and Drug Administration (FDA) in the United States [25
]. This includes an assessment of the proportion of participants with either seroconversion or significant increase in antibody titer, the fold-increase in geometric mean antibody titer (GMT) and the proportion of participants with antibody titers of 1: 40 or greater, which is associated with a 50% reduction in the risk of illness in a susceptible adult population [26
]. Typically hemagglutination inhibition (HAI) antibody titers are determined as a surrogate for neutralizing antibodies.
The results of monovalent 2009 H1N1 vaccine trials are summarized in . A single dose of unadjuvanted inactivated split-virion 2009 H1N1 vaccine containing 15μg HA led to antibody titers ≥1:40 in 95–98% of healthy adults [27
]. In children, one study found that 92.5% of 6 month-9 year olds had antibody titers ≥1:40 after a single dose of 15μg HA in an inactivated split-virion unadjuvanted 2009 H1N1 monovalent vaccine [31
], however another study found that only 47–50% of 6–35 month-olds and 65–75% of 3–9 year olds achieved these titers [32
]. After two doses, however, 90–100% children had titers ≥1:40 in both studies [31
] (). Therefore, a single dose of monovalent 2009 H1N1 vaccine was recommended in adults, but young children were recommended to receive 2 doses (reviewed by [3
]). It is likely that a single dose was sufficient to induce immunity in adults because prior exposure to seasonal H1N1 viruses had immunologically primed the population. This hypothesis is supported by studies in a mouse model of infection, where prior infection with seasonal influenza virus or seasonal LAIV primed mice for a robust response to a single dose of pandemic LAIV while unprimed mice were only partially protected against 2009 H1N1 infection with a single dose of pandemic LAIV [33
Immunogenicity of monovalent 2009 H1N1 Vaccines
The use of oil-in-water adjuvants, MF59 (Focetria, Novartis Vaccines, Italy) and AS03 (GlaxoSmithKline (GSK) Biologicals, Dresden, Germany) in 2009 H1N1 vaccines was approved by the European Medicines Agency (EMEA). The adjuvants had previously been approved in Europe for use in seasonal influenza vaccines and adjuvanted inactivated H5N1 vaccines had enabled dose sparing and induced broad cross-clade humoral responses [34
]. Their mechanism of action remains incompletely understood, however they may amplify immune responses by enhancing antigen presentation and recruiting inflammatory cells to the area of antigen deposition (reviewed by [36
Adjuvanted monovalent 2009 H1N1 vaccines permitted dose sparing (). Antibody titers ≥1:40 were induced in 92% of adults given a single dose of MF59-adjuvanted vaccine [37
] and 94–96% given the AS03-adjuvanted vaccine each containing only 3.75μg HA [38
]. In children, antibody titers ≥1:40 were induced in 100% of 6–35 month olds given 2 doses of 7.5μg or 3.75μg HA [40
] and 99.3% of 6 month-13 year olds given 1.875μg HA in adjuvanted vaccine [42
]. Moreover, in the UK, adjuvanted split-virion vaccines induced seroconversion and antibody titers ≥1:40 in a larger percentage of adults and children than non-adjuvanted whole virion vaccines [38
]. Adjuvanted influenza vaccines are, however, not licensed in the USA [43
]. Fortunately, adjuvants were not necessary to achieve adequate immunity to the 2009 H1N1 virus, though they may prove to be important in the future.
Live attenuated influenza vaccine (LAIV) viruses were also licensed for use against the 2009 H1N1 virus, however, it was necessary to introduce point mutations in the HA to optimize the yield in eggs [44
]. Intranasal vaccination with 2 doses of 107
fluorescent focus units of virus, 28 days apart, led to antibody titers ≥1:32 in 26.4% children 2–17 years old and 13.5% of adults 18–49 years old () [45
]. While these responses were modest, HAI titers are not predictive of protective efficacy of LAIV and vaccine efficacy is seen in the absence of seroconversion [46
]. Determining meaningful immune correlates of protection for LAIV is an active area of research.