Page 1261 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1222 Part ten Prevention and Therapy of Immunological Diseases

possible, and this has significantly reenergized the field. In
follow-up laboratory studies, an NIH-funded international Improved Influenza Vaccines
collaborative program that assessed the immunological correlates Seasonal influenza A imposes a significant disease burden, with
of RV144 infection risk revealed that the level of nonneutralizing the highest morbidity occurring in children and the highest
immunoglobulin G (IgG) antibody targeting a V1V2 loop antigen mortality occurring in persons over 65 years of age. The CDC
from the HIV Env gp120 protein correlated inversely with risk estimates that in the United States, annually influenza is respon-
of infection, whereas the level of IgA antibody against gp120 sible for 200 000 hospitalizations in infants and children and
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protein directly correlated with infection. The IgG antibody 3000 to 49 000 deaths (depending on the year), with 90% occur-
was capable of mediating antibody-dependent cellular cytotoxicity ring in seniors. Influenza case numbers peak in February during
(ADCC), whereas the IgA antibody competed with IgG for binding most years, and 10% of the population can become infected in
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to gp120 V2. The US National Institute of Allergy and Infectious a season. In the United States, starting from 2010, it is recom-
Diseases (NIAID)–-funded HIV Vaccine Trials Network (HVTN), mended that all persons ≥6 months of age receive an annual
the US Army, and country level and industry collaborators have influenza vaccine. If fully implemented, this would entail
formed the Pox-Protein Public-Private Partnership (also known administration of 350 million doses each year.
as “P5”) to plan an intensive series of follow-up human studies There are two types of influenza, A and B, responsible for
to confirm and fully investigate the important leads provided most human disease, and multiple subtypes of influenza A, which
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to the field by RV144. Efficacy trials that will test next-generation are categorized on the basis of the amino acid (AA) sequence
HIV vaccine regimens of clade C–expressing poxvirus vectors homology within the HA and NA proteins. Currently 19 HA
with adjuvanted protein boosts and may include DNA vector and nine NA subtypes are recognized, and these can combine
priming are being planned for southern Africa. In that region, to form many viral subtypes (e.g., H1N1, H3N2, H5N1), which
the HIV clade C (the most prevalent global clade) predominates, are further defined as specific strains based on AA sequence.
and the population has a higher risk of HIV acquisition compared Influenza B is further categorized into two lineages, Yamagata
with Thailand, where the clades E and B predominate. The coming and Victoria.
decade in HIV vaccine research will be highly interesting. Will Influenza is a negative-stranded RNA virus that lacks a proof-
the “improved versions” of the RV144 regimen provide protection reading function in its viral polymerase; hence it is highly mutable.
in southern Africa among the higher-risk, genetically distinct One of the truisms about influenza is that the only thing predict-
population of Africans exposed to C clade HIV? able about influenza is that it is unpredictable. Because of the
Discovery of a vaccine immunogen that induces broadly RNA genome mutations that continually accumulate during
neutralizing antibodies remains the holy grail of HIV vaccination. influenza replication, the WHO issues a recommendation every
Such antibodies do occur naturally in up to 15% of chronically February for a new vaccine strain composition. Vaccine manu-
infected persons, but only after years of infection. Although seen facturers in the Northern Hemisphere then race to produce the
in natural infection, no vaccine has been able to induce these year’s trivalent or quadrivalent seasonal vaccine by late summer
broadly neutralizing antibodies in vaccinated humans. However, to be ready for the winter influenza season. There are multiple
several broadly neutralizing monoclonal antibodies (mAbs) have challenges and needs with regard to this repeated (endless) annual
been cloned, and a few have been tested for safety and pharma- process of influenza vaccine prediction, production, distribution,
cokinetics in early-phase human trials. The antibody genes are implementation, uptake, and protection (Fig. 90.2).
highly mutated from their germline with ≈20–25% mutations, For the segment of the population that has the highest mortal-
indicating that extensive somatic hypermutation (SHM) has ity, that is, older adults, currently available vaccines provide only
occurred in the lymph-node germinal centers (GCs). They also relatively weak protection against influenza diagnosed with
tend to have short complementarity-determining region 1 (CDR1) polymerase chain reaction (PCR). One approach to this challenge
arms and as a result of autoreactivity against self lipids, these has been vaccination of persons ≥65 years of age with a fourfold
clones are frequently deleted. 74 higher dose of antigen, 60 µg (rather than 15 µg) for each strain
The NIAID, through two of its HIV/AIDS clinical trials based on HA protein content. This high-dose vaccine was shown
networks (the HVTN and the HIV Prevention Trials Network to increase both immunogenicity (ref) and efficacy and was
[HPTN]), is conducting a phase IIB efficacy trial of VRC01, one licensed for use in seniors in the United States. 11,12
of the broadly neutralizing mAbs. In laboratory virus neutraliza- In European and many other countries, for a number of years,
tion assays, this antibody has activity against >90% of 343 strains an oil-in-water adjuvant, MF59, has been licensed for use in
of HIV-1 across all clades at an IC80 of <1 µg/mL. 75,76 The influenza vaccine formulations specifically for seniors. The toler-
ongoing VRC01 efficacy trial (or the antibody-mediated protec- ability and safety of this adjuvanted vaccine has been demonstrated
tion [AMP] study) is a randomized, double-blind, placebo- in tens of millions of recipients, and the increases in immune
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controlled clinical trial, where the antibody will be infused response and efficacy are well documented. In 2015, on the
intravenously every other month for 18 months at doses of 0 mg/ basis of safety and antibody response data from clinical trials,
kg (placebo), 15 mg/kg, or 30 mg/kg. If the VRC01 antibody the US FDA approved this oil-in-water adjuvant, designated as
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does protect at-risk humans against HIV acquisition, this will MF59, in a formulation of an influenza vaccine for use in seniors.
provide a clear impetus to the HIV vaccine field to continue and Therefore for seasonal influenza vaccination of seniors in the
intensify efforts to develop immunogens capable of inducing United States, clinicians will now, as in many other countries,
similar or further improved broadly neutralizing antibodies. have an adjuvanted influenza vaccine option that provides
Notably, the preparation used in the VRC01 trial is a single enhanced immunogenicity.
antibody, and many experts feel that a combination of mAbs Another approach to increased protection of seniors against
targeting different epitopes on the gp120 envelope protein mortality caused by is better community (herd) immunity. The
structure may provide an even stronger result. The AMP study CDC’s ACIP recommendation for universal influenza vaccination
result is eagerly awaited. of all persons >6 months of age has the potential to reduce