Does this explain why you didn't have an article last week?
If so, it was worth it, great job Ben. Vaccine capacity should always be super high because we always need at least a baseline, and there could be some sudden time when we need much more than that.
This is such good news! Years ago I worked on a totally different malaria vaccine that was in early stage development and malaria vaccines are really difficult from a scientific perspective. Immunity to parasites is a lot more complicated than immunity to viruses or bacteria. You don't really get much in the way of sterilizing immunity to malaria, and immunity to disease wanes pretty quickly, though protection against death lasts longer. At least two of the species do antigenic variation in the blood stage, where they switch the proteins that are expressed on the surface which allows them to evade the immune response. The lifecycle is complex. Then there are the proteins. They are a lot harder to get bacteria to make because they're more complex than proteins that bacteria make so you have to use special bacteria or move to yeast or cell lines. I think malaria is a lot more interesting than viruses but it's so much more challenging.
It's also a lot more difficult to get funding for research into parasitic diseases. Parasitic worm research gets funding from veterinary medicine. Malaria doesn't have that advantage. A lot of the funding for malaria came from the military because that is a real concern in a lot of countries that the military is getting deployed to and the drugs we have can cause unpleasant side effects. (It's going to be interesting to see whether the DoD is interested in these vaccines.) I really hope this makes it easier to get funding for parasitic disease research.
If this vaccine is widely distributed, will it reduce the prevalence of Plasmodium generally, such that malaria is less common even for unvaccinated people?
Probably not. These vaccines provide decent protection against severe and fatal malaria, but they are not very good at inducing sterilizing immunity and continuing protection requires boosters. Adults who live in areas where malaria is endemic will develop immunity to disease but if you sample the blood of adults without any symptoms, many will have parasites in their blood. Natural immunity to malaria disease wanes quickly, though the protection against dying of malaria lasts much longer.
Plasmodium undergoes sexual reproduction in mosquitoes and they're infected when they feed on an infected human and that human has parasites in the gametocyte stage in their blood. The gametocytes do their sex thing and then produce the sporozoites that infect humans. There has been work on vaccines that target gametocytes but that hasn't gone very far in part because it wouldn't directly protect the person who is vaccinated because the gametocytes aren't driving diseases. Reducing the incidence of malaria is going to require vector control or engineering mosquitoes that can't be infected.
It looks like one of the five species of plasmodium that infects humans is primarily in apes, but the main one (Plasmodium falciparum) is just humans and mosquitos.
“ Five species of Plasmodium commonly infect humans. The three species associated with more severe cases are P. falciparum (which is responsible for the vast majority of malaria deaths), P. vivax, and P. knowlesi (a simian malaria that spills over into thousands of people a year). P. ovale and P. malariae generally cause a milder form of malaria.”
TBV vaccines aim to induce antibodies against functionally important proteins that are expressed on developmental stages of the parasite in the mosquito [101]. They target antigens on parasite gametes, zygotes and ookinetes [52]. The TBVs block the infection transmission from human to mosquito and so prevent malaria spreading [102]. These vaccines generate antibodies that prevent the Plasmodium sexual reproduction in the mosquito by blocking either the fertilization of the gametes, the transition of ookinete-to-oocyst, the development of the zygote into sporozoites [103, 104], or the sporozoites' invasion of the salivary gland [105].
The main transmission blocking vaccine candidates that are currently being developed include Pfs-25, Pfs-48/45, and Pfs-230 [17, 106]. Both Pfs-48/45 and Pfs-230 are gametocyte-expressed antigens that are present in human and mosquito vectors and continue forming as a protein complex on the P. falciparum gamete surface [107]. The antibodies formed against the gametocyte and its Pfs-230 and Pfs-48/45 antigens during the naturally acquired immune response have induced transmission blocking activity [108].
The major limitation of TBVs is that they do not protect the recipient from contracting malaria as they do not impede the infection route. They might be helpful in reducing disease transmission in the long run, after mass immunization has been achieved. So they could benefit the whole community and hence the terms ‘community vaccine’ and ‘altruistic vaccination’ are becoming popular [8]. However, this approach is unattractive for individuals or for Western travelers, who are the major driver of vaccine development efforts [10].
Another important limitation of TBVs is their low efficacy, because human immune mechanisms are not naturally exposed to TBV candidate antigens, and thus the boost to immunity is limited [109]. Some have proposed that malaria might adapt to a new vector, or to an alteration of certain protein compounds required for interaction with the vector [10]. In addition, because TBVs should target all individuals (including children and infants) who can transmit the disease to accomplish herd immunity, this type of mass vaccination would pose a major logistical challenge [8]. Furthermore, TBVs must have an exceptional safety profile, since they do not confer a direct benefit to the individual [17]. Hence, some have recommended their application be combined with efficacious pre-erythrocyte vaccines to prevent both infection in humans and transmission to mosquitoes, and these could also be combined with blood-stage vaccines that would add a synergistic effect by reducing onward transmission [101, 110]. Nevertheless, TBVs could still be important tools in malaria elimination and eradication programs, for preventing transmission [111].
Here’s the Take Bakery version: it costs ~$5K to save a life from malaria and yet the US government claims to be willing to spend $6M to save an American life, what is the implied welfare maximizing tax rate?
Is it any different of a solution than just more vaccines being produced elsewhere and shipped in? Africa is massive so there is still tons of logistics involved in shipping vaccines that are made one place to another
This is a bad answer, Ben. What article are you talking about? What section? If you're referring to "High risk, high reward: Gavi's investment in Africa vaccine production" - it doesn't seem to answer Sam's question.
In April 2021, the delta variant of COVID emerged in India and caused major outbreaks and deaths. As a result, India stopped all vaccine and PPE exports for a few months. Having supply located in multiple countries, ideally including some in Africa, will make Africa less vulnerable to outside events like that.
If you look at global population trends, where the human population is growing and where it's not, Africa is clearly where it's at. Our foreign policy establishment, not without reason, is focused on Asia. But in an important sense, that's already the last war, not the future. China's population is in decline. India, as long as we are friendly and not actively hostile, will do the right thing on it's own and isn't something we need to worry about.
Africa will be the focus within a few decades if not sooner. And it would be a crying shame if the United States, a country built by Africans and Europeans, and populated in significant part by their descendants, did not lay the groundwork now to make sure we are the partner of choice for emerging African countries in coming years. As opposed to leaving them open to the siren song of Russian and Chinese corruption and authoritarianism.
All of of which is to say, I hope the United States does as much as we can to promote things like availability of malaria vaccines, and vaccine production, in Africa.
Yes but I'm not sure there's any alternative to hope it's true and don't be hostile, as India will decide it's own future. The logic of the engage with China to change their values strategy did make sense, but was a little hubristic in not accounting for the fact of the US being the smaller of the two countries, as is also true with India. It would not seem wise to try to repeat that strategy with India if it came at the expense of focusing on smaller countries in Central America and Africa where there's more reason to believe it might actually work.
Also, I have to think that closer ties with emerging like-minded African countries would be healthier and possibly healing for the US domestically, simply because of the greater shared and dismal history.
The mission in Africa dwarfs anything we are doing to help people in America. The fact is we care more about ourselves. That includes progressives and liberals. We simple don’t care all that much.
Does this explain why you didn't have an article last week?
If so, it was worth it, great job Ben. Vaccine capacity should always be super high because we always need at least a baseline, and there could be some sudden time when we need much more than that.
This is such good news! Years ago I worked on a totally different malaria vaccine that was in early stage development and malaria vaccines are really difficult from a scientific perspective. Immunity to parasites is a lot more complicated than immunity to viruses or bacteria. You don't really get much in the way of sterilizing immunity to malaria, and immunity to disease wanes pretty quickly, though protection against death lasts longer. At least two of the species do antigenic variation in the blood stage, where they switch the proteins that are expressed on the surface which allows them to evade the immune response. The lifecycle is complex. Then there are the proteins. They are a lot harder to get bacteria to make because they're more complex than proteins that bacteria make so you have to use special bacteria or move to yeast or cell lines. I think malaria is a lot more interesting than viruses but it's so much more challenging.
It's also a lot more difficult to get funding for research into parasitic diseases. Parasitic worm research gets funding from veterinary medicine. Malaria doesn't have that advantage. A lot of the funding for malaria came from the military because that is a real concern in a lot of countries that the military is getting deployed to and the drugs we have can cause unpleasant side effects. (It's going to be interesting to see whether the DoD is interested in these vaccines.) I really hope this makes it easier to get funding for parasitic disease research.
So, how can we financially support this effort?
Yes. That’s what we want to know too. It looks like GIVEWELL is beginning to investigate. Any suggestions?
If this vaccine is widely distributed, will it reduce the prevalence of Plasmodium generally, such that malaria is less common even for unvaccinated people?
Probably not. These vaccines provide decent protection against severe and fatal malaria, but they are not very good at inducing sterilizing immunity and continuing protection requires boosters. Adults who live in areas where malaria is endemic will develop immunity to disease but if you sample the blood of adults without any symptoms, many will have parasites in their blood. Natural immunity to malaria disease wanes quickly, though the protection against dying of malaria lasts much longer.
Plasmodium undergoes sexual reproduction in mosquitoes and they're infected when they feed on an infected human and that human has parasites in the gametocyte stage in their blood. The gametocytes do their sex thing and then produce the sporozoites that infect humans. There has been work on vaccines that target gametocytes but that hasn't gone very far in part because it wouldn't directly protect the person who is vaccinated because the gametocytes aren't driving diseases. Reducing the incidence of malaria is going to require vector control or engineering mosquitoes that can't be infected.
As far as I'm concerned, we need those mosquitoes ASAP!
Is there a zoonotic reservoir for Plasmodium?
It looks like one of the five species of plasmodium that infects humans is primarily in apes, but the main one (Plasmodium falciparum) is just humans and mosquitos.
“ Five species of Plasmodium commonly infect humans. The three species associated with more severe cases are P. falciparum (which is responsible for the vast majority of malaria deaths), P. vivax, and P. knowlesi (a simian malaria that spills over into thousands of people a year). P. ovale and P. malariae generally cause a milder form of malaria.”
https://en.wikipedia.org/wiki/Malaria?wprov=sfti1#
My read of this is that herd immunity will require a different kind of vaccine and that it will be a huge challenge to design and deploy.
From https://tropmedhealth.biomedcentral.com/articles/10.1186/s41182-023-00516-w
Transmission blocking vaccines (TBVs) (mosquito stage vaccines):
TBV vaccines aim to induce antibodies against functionally important proteins that are expressed on developmental stages of the parasite in the mosquito [101]. They target antigens on parasite gametes, zygotes and ookinetes [52]. The TBVs block the infection transmission from human to mosquito and so prevent malaria spreading [102]. These vaccines generate antibodies that prevent the Plasmodium sexual reproduction in the mosquito by blocking either the fertilization of the gametes, the transition of ookinete-to-oocyst, the development of the zygote into sporozoites [103, 104], or the sporozoites' invasion of the salivary gland [105].
The main transmission blocking vaccine candidates that are currently being developed include Pfs-25, Pfs-48/45, and Pfs-230 [17, 106]. Both Pfs-48/45 and Pfs-230 are gametocyte-expressed antigens that are present in human and mosquito vectors and continue forming as a protein complex on the P. falciparum gamete surface [107]. The antibodies formed against the gametocyte and its Pfs-230 and Pfs-48/45 antigens during the naturally acquired immune response have induced transmission blocking activity [108].
The major limitation of TBVs is that they do not protect the recipient from contracting malaria as they do not impede the infection route. They might be helpful in reducing disease transmission in the long run, after mass immunization has been achieved. So they could benefit the whole community and hence the terms ‘community vaccine’ and ‘altruistic vaccination’ are becoming popular [8]. However, this approach is unattractive for individuals or for Western travelers, who are the major driver of vaccine development efforts [10].
Another important limitation of TBVs is their low efficacy, because human immune mechanisms are not naturally exposed to TBV candidate antigens, and thus the boost to immunity is limited [109]. Some have proposed that malaria might adapt to a new vector, or to an alteration of certain protein compounds required for interaction with the vector [10]. In addition, because TBVs should target all individuals (including children and infants) who can transmit the disease to accomplish herd immunity, this type of mass vaccination would pose a major logistical challenge [8]. Furthermore, TBVs must have an exceptional safety profile, since they do not confer a direct benefit to the individual [17]. Hence, some have recommended their application be combined with efficacious pre-erythrocyte vaccines to prevent both infection in humans and transmission to mosquitoes, and these could also be combined with blood-stage vaccines that would add a synergistic effect by reducing onward transmission [101, 110]. Nevertheless, TBVs could still be important tools in malaria elimination and eradication programs, for preventing transmission [111].
Here’s the Take Bakery version: it costs ~$5K to save a life from malaria and yet the US government claims to be willing to spend $6M to save an American life, what is the implied welfare maximizing tax rate?
What’s the logistical / public health benefit of having vaccines produced in Africa rather than made abroad and shipped in?
It avoids several supply bottlenecks and can potentially get cheaper vaccine prices for African countries.
Is it any different of a solution than just more vaccines being produced elsewhere and shipped in? Africa is massive so there is still tons of logistics involved in shipping vaccines that are made one place to another
These are good questions. For more info on the benefits and risks, check out the article I link to in the piece!
This is a bad answer, Ben. What article are you talking about? What section? If you're referring to "High risk, high reward: Gavi's investment in Africa vaccine production" - it doesn't seem to answer Sam's question.
In April 2021, the delta variant of COVID emerged in India and caused major outbreaks and deaths. As a result, India stopped all vaccine and PPE exports for a few months. Having supply located in multiple countries, ideally including some in Africa, will make Africa less vulnerable to outside events like that.
Good article....you really should check out Bjorn Lomborg...and read his book "best things first"...https://lomborg.com/best-things-first
If you look at global population trends, where the human population is growing and where it's not, Africa is clearly where it's at. Our foreign policy establishment, not without reason, is focused on Asia. But in an important sense, that's already the last war, not the future. China's population is in decline. India, as long as we are friendly and not actively hostile, will do the right thing on it's own and isn't something we need to worry about.
Africa will be the focus within a few decades if not sooner. And it would be a crying shame if the United States, a country built by Africans and Europeans, and populated in significant part by their descendants, did not lay the groundwork now to make sure we are the partner of choice for emerging African countries in coming years. As opposed to leaving them open to the siren song of Russian and Chinese corruption and authoritarianism.
All of of which is to say, I hope the United States does as much as we can to promote things like availability of malaria vaccines, and vaccine production, in Africa.
"India, as long as we are friendly and not actively hostile, will do the right thing on it's own and isn't something we need to worry about."
I really hope this is true, but its a very dangerous assumption.
Agree with your broader point that we should pay more attention to Africa as it will be a much bigger player in the future.
Yes but I'm not sure there's any alternative to hope it's true and don't be hostile, as India will decide it's own future. The logic of the engage with China to change their values strategy did make sense, but was a little hubristic in not accounting for the fact of the US being the smaller of the two countries, as is also true with India. It would not seem wise to try to repeat that strategy with India if it came at the expense of focusing on smaller countries in Central America and Africa where there's more reason to believe it might actually work.
Also, I have to think that closer ties with emerging like-minded African countries would be healthier and possibly healing for the US domestically, simply because of the greater shared and dismal history.
Great article—we should do this, but we should also do gene-drive to eliminate the Anopheles mosquito.
The mission in Africa dwarfs anything we are doing to help people in America. The fact is we care more about ourselves. That includes progressives and liberals. We simple don’t care all that much.
I really appreciate this kind of information. Thanks
The saddest victim is the last child Malaria casualty. Logistics and budgets are unemotional, but we need not be.
I very much support western aid to purchase the vaccine
And i'm okay if african countries want to invest in the production of the vaccine
I don't believe western countries should provide aid, just so they can manufacture the vaccine in africa