Influenza vaccines

a technology of influenza vaccine and antigen, applied in the field of medicine, can solve the problems of not being suited to controlling pandemics, constant antigenic changes in ha, emergence of variant or new virus strains, etc., and achieve the effects of increasing the cross-reactive immune response, reducing the potency of influenza ha-containing antigen, and reducing the risk of infection

Inactive Publication Date: 2015-04-09
KJ BIOSCI
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  • Abstract
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  • Claims
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AI Technical Summary

Benefits of technology

[0014]Therefore, the present invention provides an influenza vaccine which can not only provide an increased cross-reactive immune response and cross-protection against variant or heterologous viruses, but also a strain-specific immune response and protection against viruses contained in the vaccine like current inactivated vaccines. This vaccine comprises an influenza HA-containing antigen which is subjected to a treatment at a suitable low pH or other suitable conditions to obtain a suitable degree of loss of potency. The present invention revealed that the potency of influenza HA-containing antigens could be gradually reduced by up to 100% by low pH treatment in direct correlation with treatment conditions, and only the antigens with a suitable degree of loss of potency obtained under appropriate low pH treatment conditions induced the increased cross-reactive antibody responses and cross protection which distinctively was associated with the increased cross reaction with HA2, the highly conserved part of HA. The loss of potency may be correlated with and indicated by a functionally equivalent alternative measurement for antigenic or structural changes. These antigens can be readily formulated to meet the potency standard as a vaccine by compensating the partial potency loss with an appropriate amount of additional antigens or an adjuvant. The resulting vaccine can therefore provide the same level of strain-specific immune responses and protection against viruses contained in the vaccine as with the untreated antigen or like current inactivated vaccines, and at the same time also an increased cross-reactive immune response and cross protection against viruses not contained in the vaccine, including the possible pandemic as well as seasonal variant viruses.

Problems solved by technology

Influenza viruses undergo constant genetic changes due to its error prone replication and ability to reassort genome segments, resulting in constant antigenic changes in HA and emergence of variant or new virus strains.
The constant antigenic changes of influenza viruses pose a great challenge to developing vaccines for controlling influenza epidemics and pandemics.
Current TIVs (H1, H3, and B) are strain-specific and are not suited for controlling pandemics.
The cross-reactive antibodies against highly conserved domains can be produced by vaccination with current vaccines or after infection, but only at low levels not sufficient to provide protection.
The non-neutralizing antibodies may not prevent infection, but can reduce the incidence and severity of the disease.
However, it is a formidable task and may take a long development process before it can be approved for use in people (Nabel and Fauci, Nat Med. 16:1389-91, 2010; Rappuoli, F1000 Med Rep. 3:16, 2011).

Method used

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Examples

Experimental program
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Effect test

example 1

Potency of Inactivated Influenza Whole Virus (WV) Antigens Following Low pH Treatment

[0066]Inactivated WV antigens from three virus strains (A / New Caledonia / 20 / 99, H1 H1 (H1N1 NC); A / Wisconsin / 67 / 2005, H3N2 (H3N2 Wis); B / Malaysia / 2506 / 2004 (B Mal) were used. They were produced by purification from infected MDCK cells and inactivation with formaldehyde (1 / 4000 dilution or 0.01%) for at least three days at 4° C. The inactivation was confirmed by titration in chicken eggs and plaque assay in MDCK cells.

[0067]For low pH treatment, antigens in phosphate buffered saline (PBS, pH 7.2; ˜2.0 mg / ml) were diluted 1:10 with 20 mM sodium citrate buffers containing 150 mM NaCl (pH 4.6-5.4 in 0.2 increments) to bring the pH of antigens to 4.9-5.5 with a final antigen concentration at ˜0.2 mg / ml. The antigens were then kept at 0° C. (on ice), 4° C., 25° C. (room temperature), or 37° C. for 15 min before the pH was adjusted with an appropriate volume of 1 M Tris HCl buffer (pH 8.0) back to the origi...

example 2

Potency of Trivalent Inactivated Vaccine (TIV) Following Low pH Treatment

[0071]A TIV (Fluzone, 2006-2007) which contains the antigens from the same three virus strains described in Example 1 was also evaluated for potency after low pH treatment under different conditions. The vaccine was similarly treated, but with appropriate volumes of 0.1 M HCl added to the vaccine to adjust the pH to a similar range before neutralization with an equal volume of 0.1 M NaOH. The potency of H1N1 NC strain was measured. The results were similar to those obtained with inactivated WV antigens as described above (FIG. 1B and Table 3). However, TIV was more susceptible to low pH treatment than the WV antigen in that at any given condition, potency loss was greater with TIV. This may be related to the fact that TIV is made of split antigens. A complete potency loss (100%) was obtained at 37° C. for all pH levels tested (FIG. 1B and Table 3). Similarly, hemagglutination activity only decreased by 2 fold o...

example 3

Induction of Increased Cross-Reactive Antibody Responses by Low pH-Treated Antigens

[0073]Low pH-treated H1N1 NC WV antigens with different levels of potency loss were used to immunize 6-8 weeks old female Balb / c mice (n=7) together with the untreated control. The antigens were treated at pH 5.1 and different temperatures (0, 25, and 37° C.) and the potency (HA, μg / ml) was determined as described in Example 1. The treated antigens exhibited the potency reduction in correlation with the treatment conditions, but retained the original hemagglutination activity (Table 5).

[0074]Mice were immunized at the same antigen dose based on total proteins which was equivalent to 1 μg HA / mouse for untreated antigen by intramuscular injection twice, 4 weeks apart. A group receiving a mixture of antigens containing equal parts of the untreated antigen and the one treated at 37° C. was also included (Table 5). The mixed antigen exhibited a similar level of potency as the untreated antigen as expected ...

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Abstract

An influenza vaccine comprising an influenza hemagglutinin-containing antigen which is subjected to a treatment at a suitable low pH or other suitable conditions to obtain a suitable degree of loss of potency, and the method of making it are provided. The vaccine not only induces an increased cross-reactive immune response and cross protection, but can also induce a strain-specific immune response and protection like current inactivated vaccines. A method of administering influenza vaccines is also provided to induce an increased cross-reactive immune response and cross protection, which is especially suitable for use in emergency situations such as a pandemic.

Description

GOVERNMENT SUPPORT[0001]This invention was made with government support under Grant No. A1092923 awarded by the National Institutes of Health. The U.S. Government has certain rights in the invention.FIELD OF THE INVENTION[0002]The present invention relates generally to the field of medicine, and specifically to microbiology, immunology, and vaccines, and more specifically, influenza vaccines.BACKGROUND OF THE INVENTION[0003]There are three types of influenza viruses, A, B, and C. Influenza A and B viruses are responsible for most of infections and related diseases in humans and animals. Influenza A virus has been associated with all influenza pandemics with the latest one in 2009. Influenza viruses have two major glycoproteins anchored on its membrane envelope, hemagglutinin (HA) and neuraminidase (NA). The HA is responsible for mediating virus entry into target cells through binding to cell receptors and mediating fusion between viral and cell membranes. The HA is also the major ta...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/145C12N7/00
CPCA61K39/145C12N7/00C12N2760/16134C12N2760/16161C12N2760/16151A61K2039/5252A61K2039/525A61K39/12A61K2039/58A61K2039/70C12N2760/16234
Inventor NI, YAWEIGUO, JIANHUA
Owner KJ BIOSCI
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