Vaccine Preparedness — Are We Ready for the Next Influenza Pandemic?

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Vaccine Preparedness — Are We Ready for the Next Influenza Pandemic?

F. , M.D. Vol 358:2540-2543 June 12, 2008 Number 24.

The quest for a fully immunogenic vaccine against influenza H5N1

viruses has gone on for more than 10 years, since this family of

potentially pandemic viruses emerged as a cause of human disease in

Hong Kong in 1997. H5N1 has caused 381 human cases of influenza, with

a mortality rate exceeding 60%. H5 strains have now been found in

birds throughout much of the world (though not yet in the Americas),

and human illness has occurred in 14 countries throughout Asia and in

northern Africa.1 The much-feared rapid spread through and between

communities, however, has not occurred. Aside from small clusters of

cases within families, each human case has been associated with close

contact with poultry. The culling of poultry in the face of recognized

bird disease has been a major defense strategy since the first outbreak.

Each human infection constitutes an opportunity for genetic

modification of the virus through reassortment, mutation, or both —

modifications that could enable the virus to overcome the remaining

barrier to a pandemic by gaining the capacity for efficient

person-to-person transmission. The fact that no epidemic has yet

occurred has prompted questions about whether H5 viruses face some

insurmountable barrier of viral fitness that renders them incapable of

causing widespread illness in humans. Yet all agree that history is a

powerful teacher and that future influenza pandemics caused by novel

strains are highly probable.

So where do we stand with vaccines against emergent influenza strains?

The preparation of a vaccine against H5 influenza has not proved as

simple as adhering to the standard manufacturing techniques used to

create yearly influenza vaccines. The H5 strains have had to be

modified, since their virulence in chicken eggs causes rapid death of

the embryo, precluding the generation of an acceptable antigen yield.

Assays that are used to evaluate potential vaccine efficacy have also

had to be modified, since horse erythrocytes have proved more

sensitive than the commonly used chicken or turkey cells in measuring

responses to the H5 hemagglutinin antigen (HA). Attempts have been

made to standardize a neutralization assay in the hope that it would

be a more sensitive reflection of the functional activity of the

vaccine. The difficulties in producing and standardizing conventional

H5 vaccines have prompted innovative and extensive examinations of

options for improving all influenza vaccines.

During the pandemics of Asian influenza in 1957 and Hong Kong

influenza in 1968, there were efforts to explore possible vaccines,

but the first systematic attempt to develop vaccines against an

influenza virus representing a pandemic threat was made in the face of

the swine influenza of 1976. Both pediatric and adult trials were

conducted, studying both whole-virus and subvirion vaccines. These

trials showed that whole-virus vaccine was not only more immunogenic

but also more reactogenic than subvirion vaccine; that with a new

immunogen, two doses were needed; and that immunogenicity was roughly

doubled with a 10-fold increase in the vaccine's HA content.

These lessons, coupled with epidemiologic data on the seasonal impact

of influenza, have formed the basis for the broadening use of

influenza vaccine in the United States for yearly epidemic influenza.

The relatively poor immunogenicity of the 1976 vaccines in recipients

who had not previously been exposed to the vaccine's influenza virus

strain also presaged the difficulties of developing an effective

vaccine against H5 influenza. This history suggests that H5 may not be

a uniquely poor immunogen; rather, limited responses are to be

expected whenever people are given an entirely new influenza vaccine.

The first efforts to develop an H5 vaccine involved the testing of a

subvirion vaccine both with and without MF-59, a squalene containing

an oil-in-water emulsion. Limited immunogenicity of short duration was

seen with the subvirion vaccine, though MF-59 enhanced the antibody

response. The next study increased the dose of the subvirion vaccine

to 90 µg of HA in each of two doses. It was only at this high dose

that researchers achieved a titer that was predicted to be effective

in more than 50% of those vaccinated.2 This vaccine was approved by

the Food and Drug Administration, is being stockpiled, and has become

the benchmark against which new vaccines are judged. A vaccine

incorporating another oil-in-water adjuvant has elicited the best

immunologic responses to date and worked well even with dose-sparing

methods. As little as 3.8 µg of HA was found to induce a response in

80% of those inoculated. Conversely, baculovirus-expressed HA, a

vaccine made with alum adjuvant, and live attenuated H5 vaccines have

not increased immune responses.

The article by Ehrlich et al. in this issue of the Journal (pages

2573–2584) extends our understanding of influenza vaccines in three

key ways. Perhaps most important, it introduces the concept that

influenza vaccines may be produced in substrates other than

embryonated eggs. The idea that a vaccine might be grown in tissue

culture under controlled conditions has excited people in the field

for a number of years. Embryonated eggs are available only seasonally,

which creates a time constraint in the manufacturing of yearly vaccine

and certainly could influence preparedness for a pandemic. The

timeline for yearly vaccine production currently requires decisions to

be made in February about the subsequent winter's vaccine strains, but

with tissue-culture–grown vaccine, this schedule could be altered to

permit incorporation of late-emerging threats (see diagram).

Adaptation to efficient growth in eggs requires modifications that are

typically accomplished by inserting into the vaccine strains internal

genes from older, egg-adapted influenza strains. In the case of an H5

vaccine, it also requires modification of the HA to remove a key

virulence factor. Passage through eggs rapidly selects for changes in

the HA that have been shown to alter immunogenicity. It is difficult

to put this problem into perspective when considering an avian virus

such as H5: the vaccine's starting strain (A/Vietnam/1203/2004),

though human in origin, was egg-adapted and is at heart an avian

virus, so passage through avian eggs may not change its

immunogenicity. For nonavian strains, however, it is appealing to

consider the idea that mammalian cell culture could let us circumvent

egg adaptation and the resultant alteration in antigenicity.

Second, the vaccine that was produced was not disrupted to form a

subvirion vaccine, and Ehrlich et al. suggest that immunogenicity was

stronger as a result. Such a finding would be consistent with those of

1976 trials, but it is difficult to draw this conclusion on the basis

of comparison with published results on the H5 subvirion vaccine2

because of differences between the assays used and the ways in which

the data are presented. Something as potentially critical to global

health as the development of an H5 influenza vaccine demands a free

exchange of serologic specimens, if not head-to-head clinical trials,

so that vaccines can be directly compared. I would also caution that

given that the 1976 whole-virion vaccines caused the most marked

reactions in children, the safety data in adults cannot be directly

extrapolated to children.

Third, the study raises a key biosafety question about large-scale

production of vaccine from a wild-type virus: Could virus spread from

a production facility and initiate an epidemic? Wild-type poliovirus

strains are still used in producing inactivated polio vaccine, and the

experience with poliovirus is reassuring. In general, the closed

systems in which vaccines are produced protect the vaccine's sterility

and, in doing so, greatly limit the opportunities for spread.

Are we prepared for pandemic influenza? We are not ready to put a

vaccine in the field should H5 gain person-to-person transmissibility

or should another strain emerge. The work on novel vaccine approaches,

however, suggests that we may still make it, if influenza continues to

stay in its lair and largely confine itself to avian hosts.

Dr. reports receiving grant support from Merck,

GlaxoKline, and MedImmune. No other potential conflict of

interest relevant to this article was reported.

Source Information

Dr. is a professor of pediatrics at Dartmouth Medical School,

Hanover, NH.

References

1. World Health Organization. Cumulative number of confirmed human

cases of avian influenza A/(H5N1) reported to WHO. April 17, 2008.

(Accessed May 23, 2008, at

http://www.who.int/csr/disease/avian_influenza/country/cases_table_2008_04_17/en\

/.)

2. Treanor JJ, JD, Zangwill KM, Rowe T, Wolff M. Safety

and immunogenicity of an inactivated subvirion influenza A (H5N1)

vaccine. N Engl J Med 2006;354:1343-1351

http://content.nejm.org/cgi/content/full/358/24/2540