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* Department of Virology, Istituto Superiore di Sanità, Rome, Italy;
Institut Curie, Centre Universitaire, Unité Centre National de la Recherche Scientifique, Unité Mixte de Recherche 146, Orsay, France, and
The Edward Jenner Institute for Vaccine Research, Compton, Newbury, Berkshire, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Type I IFNs are cytokines endowed with multiple biological activities
(4). Although low levels of type I IFN are detected under
physiological conditions (5), its production is markedly
enhanced during infections (4). For a long time, the
importance of the effects of type I IFN on the immune system remained
poorly considered (6). In recent years, however, some
reports have shown that these cytokines affect the differentiation,
survival, and function of immune cells, including T cells
(7, 8, 9, 10, 11, 12, 13, 14, 15) and dendritic cells
(DCs)3
(16, 17, 18, 19, 20) and efficiently enhance a primary Ab response
(21). In a recent study it was shown that immunization of
mice with chicken 
-globulin in the presence of type I IFN results in
the generation of a potent primary immune response, characterized by an
isotype switching toward IgG2a Abs (21). In this study a
defective production of IgG2a Abs was observed in type I IFN receptor
knockout (IFN-IR KO) mice immunized in the presence of CFA. Although
this observation could suggest a role of type I IFN in the CFA-induced
immune response, it was unclear whether the most currently used
adjuvants induced type I IFN and acted through the production of these
cytokines for promoting a potentially protective Th1 immune response.
Moreover, as the effects of type I IFN on the immune response remained
controversial, with some authors emphasizing the importance of the
immunosuppressive activities of these cytokines (22), it
was essential to evaluate whether type I IFN, when administered at the
time of the vaccine injection, could act as an effective natural
adjuvant in an experimental setting in which a human vaccine and the
relevant infectious agent could be used for testing vaccine efficacy.
In the present study we used IFN-IR KO mice for investigating whether
endogenous type I IFN itself is an essential mediator in the immune
response induced after immunization with a reference protein Ag
in the presence of some of the most currently used adjuvants. Moreover,
we have evaluated the adjuvant activity of type I IFN compared with
typical adjuvants by using human influenza vaccine as a model. We found
that endogenous type I IFN is the main mediator for the promotion of
Th1-type immune responses by a wide range of adjuvants. Furthermore,
type I IFN itself was an unexpectedly powerful vaccine adjuvant for
achieving immune protection against influenza virus. These findings can
open new perspectives for vaccine development.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IFN-IR KO C3H/HeN mice were generated at the Institut Curie
(Orsay, France) as follows. The mutated allele of the original IFN-IR
KO strain (IFN-
R0/0A129) (23)
was transferred into the C3H/HeN background. Briefly, a male IFN-
R0/0A129 mouse was crossed with C3H/HeN females.
F1 females were crossed with C3H/HeN males.
Backcross progeny were crossed with C3H/HeN mice for nine generations.
From the 10th generation backcross, brother/sister mating for 10
generations produced the IFN-IR KO mice that were used for comparative
studies with identical background control C3H/HeN mice. In vitro aged
peritoneal macrophages from IFN-IR KO C3H/HeN mice were not responsive
to 800 U/ml type I IFN, as revealed by measuring inhibition of
vesicular stomatitis virus yield using procedures described previously
(5, 24), while IFN-treated peritoneal macrophages from
control mice showed a 3 log10 inhibition of virus
yield. C57BL/6 mice were purchased from Charles River (Calco, Italy).
Mice were housed in the facilities of the Department of Virology at
Istituto Superiore di Sanità and were used at the age of 7–8 wk.
Wild-type and IFN-IR KO mice were kept under specific pathogen-free
conditions. All work with animals conformed to European Community
guidelines.
Adjuvants
IFA and CFA (Sigma, St. Louis, MO) were each mixed with Ag solution at a 1/1 (v/v) ratio and emulsified, using two glass syringes and luer lock connectors, until a stable emulsion was formed. Alum (aluminum hydroxide gel, Sigma) was dissolved in the Ag solution at a ratio 1/20 (w/v), and the pH was adjusted to 6.5. After 1-h incubation at room temperature, the solution was centrifuged, and the pellet resuspended in the previous volume in saline. CpG was synthesized by Roche Diagnostic (Milan, Italy) with a phosphorothioate backbone (sequence: 5'-TsGsAsCsTsGsTsGsAsAsCsGsTsTsCsGsAsGsAsTsGsA-3'). Two hundred micrograms of CpG was dissolved in 1 ml of a solution containing 200 µg OVA. Polyinosinic-polycytidylic acid (poly(I:C); Sigma) was dissolved in saline at a concentration of 10 mg/ml, and 0.15 mg was injected i.p. in mice. MF59 (an emulsion consisting of 5% (v/v) squalene, 0.5% (v/v) Tween 80, and 0.5% (v/v) Span 85 in H2O) was provided by Chiron Vaccines (Siena, Italy) (25). MF59 was mixed with Ag solution at a 1/1 (v/v) ratio and was emulsified by pipetting.
IFN titration
The biological activity of serum IFN was determined as described previously (26). One of the units, as expressed in the text, is the equivalent of four IFN reference units.
Antigens
OVA (grade V, Sigma) was dissolved in 0.15 M NaCl and filter-sterilized before injection. The subunit influenza vaccine Agrippal, used for 1999/2000 vaccination campaign (supplied by Chiron), was prepared from influenza virus A/Beijing X127, a reassortant of influenza viruses A/Beijing/262/95 (H1N1) and A/PR/8/34 (H1N1). The hemagglutinin (HA) concentration in the subunit vaccine, calculated by single radial diffusion, was 470 µg/ml.
Interferon
High titer IFN-/ (2 x 107 U/mg
protein) was prepared in the C243-3 cell line following a method
adapted from Tovey et al. (26). IFN was concentrated and
partially purified by ammonium sulfate precipitation and dialysis
against PBS as described previously (21).
Immunizations
OVA (10 µg/mouse) with or without adjuvants was injected intradermally in a volume of 50 µl/mouse. Ten and 17 days after the first treatment, mice were boosted with OVA alone. For delayed-type hypersensitivity (DTH) assays, mice were injected with OVA and adjuvant on days 0, 10, and 17. For systemic immunization, 100 µl influenza vaccine (150 µg HA/ml) mixed with 100 µl saline, type I IFN, or adjuvant were injected i.m. into the mouse thigh. For mucosal immunization, mice were anesthetized and instilled into alternate nostrils in dropwise fashion with 50 µl of a solution containing 25 µl vaccine (470 µg HA/ml) and 25 µl saline, type I IFN, or adjuvant. Vaccination was performed on days 0 and 14.
Determination of serum Abs
To measure OVA- or influenza-specific Ab levels, standard direct ELISAs were performed. Ninety-six-well, flat-bottom microtiter plates (Immulon 4HBX, Dynatech, Chantilly, VA) were coated with 100 µl of a 1 µg/ml (for total anti-OVA IgG detection) or 4 µg/ml (for anti-OVA IgG2a and IgG1 detection) of a solution of OVA or with 3.6 µg HA/ml influenza vaccine. The following dilutions of peroxidase-conjugated secondary Abs were used for anti-OVA Ab detection: anti-mouse IgG (Fc-specific), (Sigma), 1/1,000; anti-mouse IgG2a (Cappel Research Products, Durham, NC), 1/200; and anti-mouse IgG1 (Cappel Research Products, Durham, NC), 1/400. For influenza-specific ELISA, peroxidase-conjugated secondary Abs were used as follows: anti-mouse IgG (H + L chain; Pierce, Rockford, IL), 1/75,000; anti-mouse IgG2a (Cappel), 1/200; anti-mouse IgG1 (Cappel), 1/400; and anti-mouse IgA (Kirkegaarde & Perry, Guilford, U.K.), 1/1,500. Ortho-phenylenediamine (Sigma) was used as enzymatic substrate, and plates were read in a microplate autoreader at 490 nm wavelength.
Serum hemagglutination inhibition (HAI) titers were measured according to standard procedures (27, 28).
Spleen cell proliferation assay against OVA
Preparation of spleen cell suspensions and [3H]thymidine uptake assay were performed as described previously (29). The spleen cell concentration was 5 x 105 in 0.2 ml/well of 10% FCS RPMI medium containing different concentrations of OVA (0, 50, 100, and 200 µg/ml).
OVA-specific DTH
Thirty-five days after the first injection, control and IFN-IR KO mice were challenged with OVA (20 µg/50 µl) intradermally into the right footpad, while the left footpad was injected with saline as a control. Foot swelling was measured with a microcaliper 48 h later. Data represent the mean of OVA-challenged minus saline-challenged (contralateral) foot size of three mice per group.
Virus and virus challenge
The original H1N1 A/Beijing/262/95 influenza virus (supplied by National Institute for Biological Standards and Controls, Hertfordshire, U.K.) was adapted to mouse after seven blind intranasal (i.n.) passages. The virus titer was 64 HAU/or 1.1 x 107 PFU/ml. The LD50 corresponded to a dilution of 1/1000. For virus challenge, anesthetized mice were instilled i.n. with 50 µl of a virus suspension containing 10 LD50.
Statistical analysis
Data were analyzed by the Wilcoxon rank-sum test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We first investigated whether injection of mice with currently
used adjuvants, IFA, CFA, alum, or CpG oligonucleotides (CpG), could
induce IFN and whether the integrity of the type I IFN system was
essential for the immune-promoting activity after immunization with a
protein Ag (OVA). C3H/HeN mice were treated with the different
adjuvants or poly(I:C) as a reference type I IFN inducer. Biologically
active IFN was detected in the sera of mice 24 and 48 h after the
injection of CFA or IFA. Mice injected with CpG showed increasing serum
IFN levels between 24 and 72 h, whereas no serum IFN activity was
detectable in alum-injected mice (Fig. 1
a).
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, b and c).
IFA and CFA acted as effective adjuvants for both IgG1 and IgG2a
subclasses (typically associated with Th2 and Th1 types of Ab response,
respectively), whereas CpG and alum specifically enhanced IgG2a (Th1
type) and IgG1 (Th2 type) responses, respectively. Of interest,
IFN-IR KO mice showed a marked defect in the generation of anti-OVA
Abs when CFA, IFA, or CpG was used as adjuvant. This defect was
especially pronounced with regard to the IgG2a Abs (Fig. 1, b and c). In mice immunized with alum as
adjuvant, a weak Ab response, with prevalence of IgG1 Abs, was detected
in both control and IFN-IR KO mice.
As expected, CFA, IFA, and CpG also enhanced T cell priming. Thus,
spleen cells derived from control mice immunized with OVA in the
presence of CFA, IFA, or CpG showed a higher in vitro proliferative
response to OVA compared with splenocytes from mice immunized with the
Ag alone; no significant increase in lymphocyte proliferation was
observed in animals immunized in the presence of alum (Fig. 2a). Importantly, as for the
Ab response, greatly reduced priming for lymphocyte proliferation was
detected in IFN-IR KO mice immunized with the Ag in association with
CFA, IFA, or CpG. Furthermore, while control mice immunized with the Ag
in the presence of adjuvants showed a clear-cut DTH response, no
significant response was detected in IFN-IR KO mice (Fig. 2b). These results indicate that endogenous type I IFN is
essential for the promotion of both IgG2a Ab responses (a typical
humoral hallmark of the Th1 type of immune response) and T cell
responses by a variety of adjuvants.
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To evaluate the adjuvant activity of type I IFN, we used a commercially available influenza vaccine obtained from an H1N1 influenza virus circulating in 1999–2000 (A/Beijing/262/95) and, as an infectious agent, the corresponding virus.
A single injection of vaccine together with IFN into C57BL/6 mice
resulted in a clear-cut seroconversion of all the animals. In contrast,
only a limited portion (6 of 14) of mice inoculated with the vaccine
alone seroconverted, showing Ab titers lower than those of animals
treated with vaccine and IFN (Fig. 3a, top panel).
This weak Ab response was not associated with any protection from
influenza virus infection, since all the animals died within 10 days
after challenge. In contrast, all the mice injected with the vaccine
and type I IFN were protected from virus infection (Fig. 3b,
top panel). After two injections with the vaccine alone, the
majority of mice were still not protected from virus challenge (Fig. 3b, bottom panel). Two immunizations with the
vaccine mixed with IFN resulted in a homogeneous increase in Ab titers
in all the mice (Fig. 3a, bottom panel).
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c, top
panel). Two weeks after the second immunization, mice immunized
with the vaccine together with IFN showed higher levels of serum IgA
than animals injected with vaccine alone. Moreover, only sera from
IFN-treated mice exhibited detectable HAI titers (Fig. 3c,
bottom panel).
The adjuvant effect of type I IFN on the Ab response to influenza
vaccine (total Igs and IgG2a) was dose dependent (Fig. 4a) and paralleled a
dose-dependent protection from virus challenge (Fig. 4b). Of
interest, in mice immunized with the vaccine together with the highest
dose of IFN (2 x 105 U), there was complete
protection, as evaluated not only by the survival data, but also by the
lack of any virus-induced decrease in mouse weight. Mice injected with
2 x 104 U IFN survived after virus
challenge, but a transient decrease in body weight after infection was
observed. Only a low level of protection was detected in animals
immunized with the vaccine together with the lowest dose of IFN (2
x 103 U; Fig. 4b). Additional IFN
injections on days 1 and 2 markedly enhanced the Ab response (total
IgGs and IgG2a) with respect to levels found in mice only coinjected
with IFN and vaccine on day 0 (Fig. 4c). Notably, mice
subjected to a single IFN injection either before or after vaccine
inoculation developed much lower Ab titers than animals coinjected with
the vaccine and the cytokine (Fig. 4d) and were not
protected from virus challenge (data not shown). The adjuvant potency
of type I IFN in protecting mice from a lethal challenge with influenza
virus was comparable to that obtained with two of the best currently
available adjuvants (CFA and MF59), while alum was ineffective (Fig. 4e).
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After a first immunization, while induction of total Igs and IgG1 Abs
was similar in animals immunized with either MF59 or IFN as adjuvants,
only IFN-treated mice showed high levels of serum IgG2a Abs (Fig. 5a, top). Of interest, control mice immunized
with the vaccine alone showed detectable levels of IgA Abs, which were
not revealed in IFN-IR KO mice, suggesting that endogenous IFN played a
role in the induction of IgA in the early phase of the immune response.
After the second immunization, there was an increase in Ab production
in all vaccinated control mice. Interestingly, while IgG1 levels were
higher in mice treated with MF59, considerable IgG2a titers were only
detected in IFN-treated animals (Fig. 5, bottom). Likewise,
IFN-IR KO mice immunized with MF59 as an adjuvant did not show any
level of IgG2a Abs, further indicating a selective role of type I IFN
for IgG2a induction. Notably, no adjuvant effect on IgA Abs was
observed in IFN-IR KO mice immunized in the presence of either type I
IFN or MF59 (Fig. 5, bottom), suggesting that type I IFN is
important for a sustained IgA production.
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Identification of mucosal adjuvants is an important task of
vaccine research, since induction of protective mucosal immunity is
crucial for achieving local immune protection at the pathogen entry
site. In a first set of experiments we immunized C57BL/6 mice by giving
two i.n. administrations, 14 days apart, of influenza vaccine alone or
mixed with type I IFN; Ab levels were measured 2 wk after each
immunization (Fig. 6a). A
general increase in Ab production (especially IgG2a) was detectable in
IFN-treated animals after the first immunization. Two weeks after the
second immunization, there was a further increase in Ab titers in
IFN-treated mice compared with animals injected with the vaccine alone.
Notably, at this time point, an impressive increase in IgG2a and IgA
titers (1000- and 100-fold, respectively) was observed in animals
immunized with the vaccine mixed with IFN compared with mice injected
with vaccine alone. Mice immunized with IFN as an adjuvant also showed
higher levels of secretory pulmonary IgA than control animals. Of
interest, all mice given the IFN-adjuvanted vaccine i.n. were protected
from influenza virus infection, as revealed by both survival values and
lack of decrease in mouse weight after challenge, while only a
partially protective effect was found in animals immunized with vaccine
alone (Fig. 6b). In a similar immunization experiment in
IFN-IR KO and control C3H/HeN mice, type I IFN proved to be superior to
MF59 in inducing IgG2a and IgA in control animals at both time points,
while MF59 was more effective in inducing IgG1 Abs after two
immunizations (Fig. 6c, bottom). As expected, no
significant Ab response for all Ig subclasses was observed in IFN-IR KO
animals immunized i.n. with IFN as adjuvant. In contrast, MF59 was
still capable of inducing IgG1 Abs in IFN-IR KO mice, but the induction
of IgG2a and IgA was largely abrogated compared with the response
detected in control animals (Fig. 6c).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-galactosidase together with CpG as adjuvant,
suggesting that type I IFN is required to mount an adaptive response to
immunostimulatory DNA (30). Notably, our results obtained
in the influenza vaccine model show that type I IFN was unexpectedly
effective in inducing rapid seroconversion in all the animals,
characterized by selective induction of high levels of IgG2a even after
a single immunization, resulting in full protection from virus
challenge. IgG2a Abs are characteristic of the response to virus infection, are often protective, and demonstrate neutralizing activity (31). Thus, we may assume that in the course of a virus infection the expression of type I IFN and generation of IgG2a Abs are linked events of biological relevance for the subsequent generation of protective immunity.
When given i.m. as adjuvant, type I IFN was far superior to alum and was equivalent to CFA, considered one of the most powerful adjuvants in animal models, and to MF59, a new adjuvant recently considered the best candidate for anti-influenza vaccination in elderly individuals (32). Of interest, while these typical adjuvants have been used at the maximal tolerated dose, IFN dosages higher than those used in our experiments could result in even more potent adjuvant activity. Notably, two subsequent treatments with IFN on days 1 and 2 further increased the level of IgG2a Ab, while a single IFN injection at a time different from that of vaccine administration was ineffective. Thus, the optimal adjuvant activity is obtained under conditions mimicking the natural response to viral infections, often resulting in long term immunity, where considerable levels of type I IFN are produced at early times after virus contact with specific host cells, such as the so-called natural IFN-producing cells (also named pDC2 or plasmocytoid DCs), considered professional cells for producing high IFN levels in response to viral challenge (33, 34).
One of the major issues in vaccine research is the definition of strategies for inducing mucosal immunity and IgA production, which are important for immune protection against infectious agents transmitted through the respiratory system (35). In this regard it is of special interest that i.n. injection of influenza vaccine with IFN was particularly effective in inducing serum IgG2a and IgA Abs and full protection from virus challenge. Type I IFN was superior to MF59 in inducing IgG2a and IgA Abs when used as an i.n. adjuvant. This study reports the first evidence indicating that type I IFN is important for IgA production and for the establishment of mucosal immunity. Recent studies have shown that the i.n. administration of type I IFN represents an effective delivery system for inducing therapeutic effects with these cytokines (36). However, the mechanisms of action are still unclear (37). Thus, the present finding showing that the i.n. administration of IFN is unusually effective in enhancing vaccine efficacy and inducing immune correlates of protection encourages further studies for understanding whether type I IFN can represent a crucial factor in breaking tolerance and inducing mucosal immunity.
With regard to the role of endogenous type I IFN in the immune response to influenza vaccine, our results indicate that the induction of IgG2a and IgA Abs is mostly mediated by type I IFN itself, since no or poor production of these Abs was observed in IFN-IR KO mice. Early studies had shown that low levels of spontaneous type I IFN can be responsible for the natural antiviral state of macrophages (5) as well as for host-mediated restriction of tumor growth in mice transplanted with syngeneic IFN-resistant tumor cells (38), supporting the concept that even basal IFN levels can play important in vivo roles. Thus, we may argue that even in the absence of specific IFN induction, the defective response to the i.n. immunization of IFN-IR KO mice with influenza vaccine is indicative of the importance of type I IFN basal levels in the generation of a specific humoral immune response.
Identification of new adjuvants is an urgent need for vaccine development and especially for subunit vaccines, which are poorly immunogenic. The use of adjuvants effective in animal models is often restricted by safety concerns. The finding that type I IFNs, cytokines with a long record of clinical use (39, 40), are necessary and sufficient to induce a protective immune response to vaccines is not only important for the comprehension of the mechanisms underlying the immune response to infections, but can also exhibit practical implications for new strategies in vaccine development. As differences in the type I IFN-mediated regulation of the Th1 responses between mice and humans have been reported (41), the possible transference to humans of data obtained in mouse models should be regarded with caution. Selected clinical trials are needed to establish whether type I IFN can represent valuable natural adjuvants for human vaccines.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Enrico Proietti, Laboratory of Virology, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy. E-mail address: proietti{at}iss.it
3 Abbreviations used in this paper: DC, dendritic cells; DTH, delayed-type hypersensitivity; HA, hemagglutinin; HAI, hemagglutination inhibition; IFN-IR KO, type I IFN receptor knockout; i.n., intranasal, intranasally; poly(I:C), polyinosinic-polycytidylic acid.
Received for publication November 14, 2001. Accepted for publication May 6, 2002.
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A. S. Hidmark, G. M. McInerney, E. K. L. Nordstrom, I. Douagi, K. M. Werner, P. Liljestrom, and G. B. K. Hedestam Early Alpha/Beta Interferon Production by Myeloid Dendritic Cells in Response to UV-Inactivated Virus Requires Viral Entry and Interferon Regulatory Factor 3 but Not MyD88 J. Virol., August 15, 2005; 79(16): 10376 - 10385. [Abstract] [Full Text] [PDF]
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M. Quinlivan, D. Zamarin, A. Garcia-Sastre, A. Cullinane, T. Chambers, and P. Palese Attenuation of Equine Influenza Viruses through Truncations of the NS1 Protein J. Virol., July 1, 2005; 79(13): 8431 - 8439. [Abstract] [Full Text] [PDF]
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B. Ferko, J. Stasakova, J. Romanova, C. Kittel, S. Sereinig, H. Katinger, and A. Egorov Immunogenicity and Protection Efficacy of Replication-Deficient Influenza A Viruses with Altered NS1 Genes J. Virol., December 1, 2004; 78(23): 13037 - 13045. [Abstract] [Full Text] [PDF]
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G. Schiavoni, C. Mauri, D. Carlei, F. Belardelli, M. Castellani Pastoris, and E. Proietti Type I IFN Protects Permissive Macrophages from Legionella pneumophila Infection through an IFN-{gamma}-Independent Pathway J. Immunol., July 15, 2004; 173(2): 1266 - 1275. [Abstract] [Full Text] [PDF]
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N. Chaput, N. E. C. Schartz, F. Andre, J. Taieb, S. Novault, P. Bonnaventure, N. Aubert, J. Bernard, F. Lemonnier, M. Merad, et al. Exosomes as Potent Cell-Free Peptide-Based Vaccine. II. Exosomes in CpG Adjuvants Efficiently Prime Naive Tc1 Lymphocytes Leading to Tumor Rejection J. Immunol., February 15, 2004; 172(4): 2137 - 2146. [Abstract] [Full Text] [PDF]
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B. Bossert, S. Marozin, and K.-K. Conzelmann Nonstructural Proteins NS1 and NS2 of Bovine Respiratory Syncytial Virus Block Activation of Interferon Regulatory Factor 3 J. Virol., August 15, 2003; 77(16): 8661 - 8668. [Abstract] [Full Text] [PDF]
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J.-F. Valarcher, J. Furze, S. Wyld, R. Cook, K.-K. Conzelmann, and G. Taylor Role of Alpha/Beta Interferons in the Attenuation and Immunogenicity of Recombinant Bovine Respiratory Syncytial Viruses Lacking NS Proteins J. Virol., August 1, 2003; 77(15): 8426 - 8439. [Abstract] [Full Text] [PDF]
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 C. Lapenta, S. M. Santini, M. Logozzi, M. Spada, M. Andreotti, T. Di Pucchio, S. Parlato, and F. Belardelli Potent Immune Response against HIV-1 and Protection from Virus Challenge in hu-PBL-SCID Mice Immunized with Inactivated Virus-pulsed Dendritic Cells Generated in the Presence of IFN-{alpha} J. Exp. Med., July 21, 2003; 198(2): 361 - 367. [Abstract] [Full Text] [PDF]
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or open bars, mice treated with FLU vaccine;
or filled bars, mice treated with FLU vaccine plus IFN.
, mice treated with FLU vaccine alone; 
,
mice treated with FLU vaccine plus IFN (2 x 103
U/mouse); 
, mice treated with FLU vaccine plus IFN (2 x
104 U/mouse); 
