1. A semiconductor integrated circuit comprising:
a boost circuit configured to boost a power supply voltage so as to generate first and second voltages, the second voltage being lower than the first voltage;
a load circuit supplied with the first voltage; and
a capacitor having: first and second diffusion regions formed in a state of separating from each other in a semiconductor substrate; a first insulating film formed on a channel region between the first and second diffusion regions; a first electrode formed on the first insulating film; a second insulating film formed on the first electrode; and a second electrode formed on the second insulating film, and comprising a transistor,
the second voltage being applied to the first electrode,
the power supply voltage being applied to the second electrode,
the first voltage being applied to at least one of the first and second diffusion regions.
2. The circuit according to claim 1, wherein the first voltage is higher than each breakdown voltage of the first and second insulating films.
3. The circuit according to claim 1, wherein
the load circuit includes an electrically rewritable memory cell,
the memory cell has:
third and fourth diffusion regions formed in a state of separating from each other in the semiconductor substrate;
a gate insulating film formed on the semiconductor substrate between the third and fourth diffusion regions;
a floating gate electrode formed on the gate insulating film;
an intergate insulating film formed on the floating gate electrode; and
a control gate electrode formed on the intergate insulating film,
the first insulating film has the same breakdown voltage as the gate insulating film, and
the second insulating film has the same breakdown voltage as the intergate insulating film.
4. The circuit according to claim 1, wherein
the boost circuit comprises a charge pump, and includes a plurality of units each composed of a diode-connected transistor and a capacitor,
the first voltage is output from the final unit, and
the second voltage is output from a unit prior to the final unit.
5. The circuit according to claim 1, wherein the boost circuit includes:
a first boost circuit configured to boost the power supply voltage so as to generate the first voltage; and
a second boost circuit configured to boost the power supply voltage so as to generate the second voltage.
6. A semiconductor integrated circuit comprising:
a boost circuit configured to boost a power supply voltage so as to generate first and second voltages, the second voltage being lower than the first voltage;
a load circuit supplied with the first voltage; and
a capacitor having: first and second diffusion regions formed in a state of separating from each other in a semiconductor region; a first insulating film formed on a channel region between the first and second diffusion regions; a first electrode formed on the first insulating film; a second insulating film formed on the first electrode; and a second electrode formed on the second insulating film, and comprising a transistor, the semiconductor region, the first and second diffusion regions being the same conductivity type,
the second voltage being applied to the first electrode,
the power supply voltage being applied to the second electrode,
the first voltage being applied to at least one of the first and second diffusion regions.
7. The circuit according to claim 6, wherein the first voltage is higher than each breakdown voltage of the first and second insulating films.
8. The circuit according to claim 6, wherein
the load circuit includes an electrically rewritable memory cell,
the memory cell has:
third and fourth diffusion regions formed in a state of separating from each other in a semiconductor substrate;
a gate insulating film formed on the semiconductor substrate between the third and fourth diffusion regions;
a floating gate electrode formed on the gate insulating film;
an intergate insulating film formed on the floating gate electrode; and
a control gate electrode formed on the intergate insulating film,
the first insulating film has the same breakdown voltage as the gate insulating film, and
the second insulating film has the same breakdown voltage as the intergate insulating film.
9. The circuit according to claim 6, wherein
the boost circuit comprises a charge pump, and includes a plurality of units each composed of a diode-connected transistor and a capacitor,
the first voltage is output from the final unit, and
the second voltage is output from a unit prior to the final unit.
10. The circuit according to claim 6, wherein the boost circuit includes:
a first boost circuit configured to boost the power supply voltage so as to generate the first voltage; and
a second boost circuit configured to boost the power supply voltage so as to generate the second voltage.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A composition comprising:
isolated antigenic outer membrane vesicles (OMVs) or microvesicles (MVs) prepared from a first Neisseria meningitidis that is genetically modified:
(a) to comprise a mutation in a gene involved in biosynthesis or modification of lipid A of its lipopolysaccharide and
(b) to overexpress a meningococcal GNA1870 polypeptide, wherein the overexpression consists of the overexpression of a full-length meningococcal GNA1870 polypeptide in the OMVs or the MVs at a level that is greater than 3 to 10 times the level of the endogenous GNA1870 polypeptide expressed by unmodified parental Neisseria meningitidis from which the first genetically modified first Neisseria meningitidis is obtained,
wherein the OMVs or the MVs are prepared without using a detergent, and the composition when administered to a mammalian subject, elicits serum antibodies specific to the overexpressed GNA1870 polypeptide that are bactericidal against at least three Neisseria meningitidis strains that express a GNA1870 polypeptide and a heterologous meningococcal PorA protein, and
a pharmaceutically acceptable carrier.
2. The composition of claim 1, wherein the lipopolysaccharide of the genetically modified Neisseria meningitidis has no detectable toxic activity of lipid A or decreased toxic activity of lipid A relative to its wild-type lipid A.
3. The composition of claim 1, wherein the mutation comprises a mutation in htrB gene, msbB gene, or lpxK gene.
4. The composition of claim 1, wherein the overexpressed GNA1870 polypeptide is overexpressed at a level that is four or more times greater than the level of the endogenous GNA1870 polypeptide expressed by the unmodified parental Neisseria meningitidis from which the first genetically modified Neisseria meningitidis is obtained.
5. The composition of claim 1, wherein the overexpressed GNA1870 polypeptide is overexpressed at a level that is five or more times greater than the level of the endogenous GNA1870 polypeptide expressed by the unmodified parental Neisseria meningitidis from which the first genetically modified Neisseria meningitidis is obtained.
6. The composition of claim 1, wherein the overexpressed GNA1870 polypeptide is overexpressed at a level that is six or more times greater than the level of the endogenous GNA1870 polypeptide expressed by the unmodified parental Neisseria meningitidis from which the first genetically modified Neisseria meningitidis is obtained.
7. The composition of claim 1, wherein the overexpressed GNA1870 polypeptide is overexpressed at a level that is seven or more times greater than the level of the endogenous GNA1870 polypeptide expressed by the unmodified parental Neisseria meningitidis from which the first genetically modified Neisseria meningitidis is obtained.
8. The composition of claim 1, wherein the overexpressed GNA1870 polypeptide is overexpressed at a level that is eight or more times greater than the level of the endogenous GNA1870 polypeptide expressed by the unmodified parental Neisseria meningitidis from which the first genetically modified Neisseria meningitidis is obtained.
9. The composition of claim 1, wherein the overexpressed GNA1870 polypeptide is overexpressed at a level that is nine or more times greater than the level of the endogenous GNA1870 polypeptide expressed by the unmodified parental Neisseria meningitidis from which the first genetically modified Neisseria meningitidis is obtained.
10. The composition of claim 1, wherein the overexpressed GNA1870 polypeptide is overexpressed at a level that is ten or more times greater than the level of the endogenous GNA1870 polypeptide expressed by the unmodified parental Neisseria meningitidis from which the first genetically modified Neisseria meningitidis is obtained.
11. The composition of claim 1, wherein the composition further comprises:
isolated antigenic outer membrane vesicles (OMVs) or microvesicles (MVs) prepared from a second Neisseria meningitidis that is genetically modified to overexpress a meningococcal GNA1870 polypeptide, wherein the overexpression consists of the overexpression of a heterologous full-length meningococcal GNA1870 polypeptide in the OMVs or the MVs at a level that is greater than 3 times the level of the endogenous GNA1870 polypeptide expressed by unmodified parental Neisseria meningitidis from which the second genetically modified Neisseria meningitidis is obtained, wherein the OMVs or the MVs are prepared without using a detergent, and the composition when administered to a mammalian subject, elicits serum antibodies specific to the GNA1870 polypeptide overexpressed by the second genetically modified Neisseria meningitidis and wherein the antibodies are bactericidal against at least three Neisseria meningitidis strains that express a GNA1870 polypeptide and a heterologous meningococcal PorA protein, wherein the second Neisseria meningitidis bacterium is genetically diverse to the first Neisseria meningitidis bacterium.
12. The composition of claim 11, wherein the first and the second Neisseria meningitidis are genetically diverse in that the two Neisseria meningitidis differ in at least one of serogroup, serotype, or subserotype.
13. The composition of claim 1, wherein the first Neisseria meningitidis is genetically modified to produce at least two different meningococcal GNA1870 polypeptides of different variant groups.
14. The composition of claim 1, wherein the first Neisseria meningitidis is genetically modified to disrupt the production of the endogenous GNA1870 polypeptide.
15. The composition of claim 11, wherein the second Neisseria meningitidis is genetically modified to disrupt the production of the endogenous GNA1870 polypeptide.
16. A method of producing the composition of claim 1, the method comprising:
culturing the genetically modified first Neisseria meningitidis;
preparing the OMVs or the MVs from the culture; and
combining the OMVs or the MVs with the pharmaceutically acceptable carrier to produce the composition.
17. A method of producing the composition of claim 2, the method comprising:
culturing the genetically modified first Neisseria meningitidis;
preparing the OMVs or the MVs from the culture; and
combining the OMVs or the MVs with the pharmaceutically acceptable carrier to produce the composition.
18. A method of producing the composition of claim 10, the method comprising:
culturing the genetically modified first Neisseria meningitidis;
preparing the OMVs or the MVs from the culture; and
combining the OMVs or the MVs with the pharmaceutically acceptable carrier to produce the composition.
19. A method of producing the composition of claim 11, the method comprising:
culturing the genetically modified first and the second Neisseria meningitidis;
preparing the OMVs or the MVs from each of the cultures; and
combining the OMVs or the MVs with the pharmaceutically acceptable carrier to produce the composition.
20. A method of eliciting a bactericidal immune response against Neisseria meningitidis in a mammalian subject, the method comprising administering to the mammalian subject an immunologically effective amount of the composition of claim 1.
21. A method of eliciting a bactericidal immune response against Neisseria meningitidis in a mammalian subject, the method comprising administering to the mammalian subject an immunologically effective amount of the composition of claim 2.
22. A method of eliciting a bactericidal immune response against Neisseria meningitidis in a mammalian subject, the method comprising administering to the mammalian subject an immunologically effective amount of the composition of claim 4.
23. A method of eliciting a bactericidal immune response against Neisseria meningitidis in a mammalian subject, the method comprising administering to the mammalian subject an immunologically effective amount of the composition of claim 10.
24. A method of eliciting a bactericidal immune response against Neisseria meningitidis in a mammalian subject, the method comprising administering to the mammalian subject an immunologically effective amount of the composition of claim 11.