Viruses can protect mice from malaria

Plasmodium sporozoite

Credit: Ute Frevert

and Margaret Shear

In a new study, genetically altered viruses produced long-lasting antimalaria antibodies in mice and protected many of them from the disease.

The approach, known as vector immunoprophylaxis (VIP), produced antibodies against the Plasmodium falciparum circumsporozoite protein (CSP) and prevented malaria infection in 10% to 100% of mice, depending on the dose and type of viral vector used.

Researchers recounted these results in PNAS.

“We need better ways to fight malaria,” said study author Gary Ketner, PhD, of the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland. “And our research suggests [VIP] could be a promising approach.”

To test the approach, Dr Ketner and his colleagues constructed adeno-associated virus (AAV) vectors encoding human immunoglobulin G (hIgG) specific for the P falciparum CSP central repeat by inserting the variable regions of mouse monoclonal antibodies (mAbs) 2A10 and 2C11 into the hIgG framework of the VIP expression plasmid.

The team then injected mice with 1 x 10¹¹ genome copies (GC) of 2A10-AAV, 2C11-AAV, b12-AAV (which protects against HIV), or with buffer.

Within a week, the AAV-transduced mice expressed hIgG at 50 μg/mL to 500 μg/mL in serum. The expression increased until about the 4-week mark, when it reached 1000 μg/mL in some mice.

The mice that received 2A10-AAV or 2C11-AAV expressed antibodies that bound recombinant CSP and recognized whole P falciparum sporozoites. The b12-AAV-transduced mice and buffer-transduced mice did not.

In all AAV-transduced mice, serum antibody concentrations plateaued at 4 to 8 weeks and remained at that level through the end of the study, which was 52 weeks after transduction.

At the 8-week mark, the researchers tested the efficacy of VIP. They introduced—either intravenously or through a mosquito-bite challenge—transgenic Plasmodium berghei rodent sporozoites that incorporate the P falciparum target of the antibody in their CSP.

In the intravenously challenged group, 70% of 2A10-AAV-transduced mice were protected from malaria. In the mosquito-bite-challenged group, 60% of 2A10-AAV-transduced mice and 30% of 2C11-AAV-transduced mice were protected from malaria.

Role of dose and antibody level

To examine the effects of vector dose on mAb production and malaria protection, the researchers compared varying doses of 2A10-AAV to b12-AAV. They tested mice transduced with 3 x 10¹¹ GC of b12-AAV or doses of 2A10-AAV ranging from 3 x 10⁹ GC to 3 x 10¹¹ GC.

The team conducted a mosquito-bite challenge at 11 weeks after transduction. And they found that 70% of the mice that received the highest AAV dose (1 x 10¹¹ GC) were protected, as were 40% of mice that received 3 x 10¹⁰ GC and 10% of mice that received 1 x 10¹⁰ GC.

All mice transduced with 3 x 10⁹ GC were parasitemic by day 7, and all b12-AAV mice were parasitemic by day 6. There was a signficant correlation between 2A10 antibody concentration and day to parasitemia.

In a subset of mice that produced higher levels of antibodies, the antimalaria protection was 100%. These mice expressed CSP-specific mAb 2A10 at 1 mg/mL or more.

So it seems the protection from malaria is dose-dependent, said study author Cailin Deal, PhD, of the Ragon Institute of MGH, MIT and Harvard in Cambridge, Massachusetts.

“Of course, we don’t know what the human dosage would be,” she added, “but it’s conceivable that the right dosage could completely protect against malaria.”

Plasmodium sporozoite

Credit: Ute Frevert

and Margaret Shear

In a new study, genetically altered viruses produced long-lasting antimalaria antibodies in mice and protected many of them from the disease.

The approach, known as vector immunoprophylaxis (VIP), produced antibodies against the Plasmodium falciparum circumsporozoite protein (CSP) and prevented malaria infection in 10% to 100% of mice, depending on the dose and type of viral vector used.

Researchers recounted these results in PNAS.

“We need better ways to fight malaria,” said study author Gary Ketner, PhD, of the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland. “And our research suggests [VIP] could be a promising approach.”

To test the approach, Dr Ketner and his colleagues constructed adeno-associated virus (AAV) vectors encoding human immunoglobulin G (hIgG) specific for the P falciparum CSP central repeat by inserting the variable regions of mouse monoclonal antibodies (mAbs) 2A10 and 2C11 into the hIgG framework of the VIP expression plasmid.

The team then injected mice with 1 x 10¹¹ genome copies (GC) of 2A10-AAV, 2C11-AAV, b12-AAV (which protects against HIV), or with buffer.

Within a week, the AAV-transduced mice expressed hIgG at 50 μg/mL to 500 μg/mL in serum. The expression increased until about the 4-week mark, when it reached 1000 μg/mL in some mice.

The mice that received 2A10-AAV or 2C11-AAV expressed antibodies that bound recombinant CSP and recognized whole P falciparum sporozoites. The b12-AAV-transduced mice and buffer-transduced mice did not.

In all AAV-transduced mice, serum antibody concentrations plateaued at 4 to 8 weeks and remained at that level through the end of the study, which was 52 weeks after transduction.

At the 8-week mark, the researchers tested the efficacy of VIP. They introduced—either intravenously or through a mosquito-bite challenge—transgenic Plasmodium berghei rodent sporozoites that incorporate the P falciparum target of the antibody in their CSP.

In the intravenously challenged group, 70% of 2A10-AAV-transduced mice were protected from malaria. In the mosquito-bite-challenged group, 60% of 2A10-AAV-transduced mice and 30% of 2C11-AAV-transduced mice were protected from malaria.

Role of dose and antibody level

To examine the effects of vector dose on mAb production and malaria protection, the researchers compared varying doses of 2A10-AAV to b12-AAV. They tested mice transduced with 3 x 10¹¹ GC of b12-AAV or doses of 2A10-AAV ranging from 3 x 10⁹ GC to 3 x 10¹¹ GC.

The team conducted a mosquito-bite challenge at 11 weeks after transduction. And they found that 70% of the mice that received the highest AAV dose (1 x 10¹¹ GC) were protected, as were 40% of mice that received 3 x 10¹⁰ GC and 10% of mice that received 1 x 10¹⁰ GC.

All mice transduced with 3 x 10⁹ GC were parasitemic by day 7, and all b12-AAV mice were parasitemic by day 6. There was a signficant correlation between 2A10 antibody concentration and day to parasitemia.

In a subset of mice that produced higher levels of antibodies, the antimalaria protection was 100%. These mice expressed CSP-specific mAb 2A10 at 1 mg/mL or more.

So it seems the protection from malaria is dose-dependent, said study author Cailin Deal, PhD, of the Ragon Institute of MGH, MIT and Harvard in Cambridge, Massachusetts.

“Of course, we don’t know what the human dosage would be,” she added, “but it’s conceivable that the right dosage could completely protect against malaria.”

Plasmodium sporozoite

Credit: Ute Frevert

and Margaret Shear

In a new study, genetically altered viruses produced long-lasting antimalaria antibodies in mice and protected many of them from the disease.

The approach, known as vector immunoprophylaxis (VIP), produced antibodies against the Plasmodium falciparum circumsporozoite protein (CSP) and prevented malaria infection in 10% to 100% of mice, depending on the dose and type of viral vector used.

Researchers recounted these results in PNAS.

“We need better ways to fight malaria,” said study author Gary Ketner, PhD, of the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland. “And our research suggests [VIP] could be a promising approach.”

To test the approach, Dr Ketner and his colleagues constructed adeno-associated virus (AAV) vectors encoding human immunoglobulin G (hIgG) specific for the P falciparum CSP central repeat by inserting the variable regions of mouse monoclonal antibodies (mAbs) 2A10 and 2C11 into the hIgG framework of the VIP expression plasmid.

The team then injected mice with 1 x 10¹¹ genome copies (GC) of 2A10-AAV, 2C11-AAV, b12-AAV (which protects against HIV), or with buffer.

Within a week, the AAV-transduced mice expressed hIgG at 50 μg/mL to 500 μg/mL in serum. The expression increased until about the 4-week mark, when it reached 1000 μg/mL in some mice.

The mice that received 2A10-AAV or 2C11-AAV expressed antibodies that bound recombinant CSP and recognized whole P falciparum sporozoites. The b12-AAV-transduced mice and buffer-transduced mice did not.

In all AAV-transduced mice, serum antibody concentrations plateaued at 4 to 8 weeks and remained at that level through the end of the study, which was 52 weeks after transduction.

At the 8-week mark, the researchers tested the efficacy of VIP. They introduced—either intravenously or through a mosquito-bite challenge—transgenic Plasmodium berghei rodent sporozoites that incorporate the P falciparum target of the antibody in their CSP.

In the intravenously challenged group, 70% of 2A10-AAV-transduced mice were protected from malaria. In the mosquito-bite-challenged group, 60% of 2A10-AAV-transduced mice and 30% of 2C11-AAV-transduced mice were protected from malaria.

Role of dose and antibody level

To examine the effects of vector dose on mAb production and malaria protection, the researchers compared varying doses of 2A10-AAV to b12-AAV. They tested mice transduced with 3 x 10¹¹ GC of b12-AAV or doses of 2A10-AAV ranging from 3 x 10⁹ GC to 3 x 10¹¹ GC.

The team conducted a mosquito-bite challenge at 11 weeks after transduction. And they found that 70% of the mice that received the highest AAV dose (1 x 10¹¹ GC) were protected, as were 40% of mice that received 3 x 10¹⁰ GC and 10% of mice that received 1 x 10¹⁰ GC.

All mice transduced with 3 x 10⁹ GC were parasitemic by day 7, and all b12-AAV mice were parasitemic by day 6. There was a signficant correlation between 2A10 antibody concentration and day to parasitemia.

In a subset of mice that produced higher levels of antibodies, the antimalaria protection was 100%. These mice expressed CSP-specific mAb 2A10 at 1 mg/mL or more.

So it seems the protection from malaria is dose-dependent, said study author Cailin Deal, PhD, of the Ragon Institute of MGH, MIT and Harvard in Cambridge, Massachusetts.

“Of course, we don’t know what the human dosage would be,” she added, “but it’s conceivable that the right dosage could completely protect against malaria.”