Archive for the 'Vaccine' Category

Patent thickets in malaria vaccine development

If next-stage malaria vaccines work (the primary challenge), they are likely to be based on multiple antigens, adjuvants, and other vaccine technology platforms.  Will intellectual property limitations, in the form of competing claims across a number of public and private players (the aptly named patent thicket), impede their development, commercialization, or access? Here’s a neat Rockefeller funded report for the Malaria Vaccine Initiative – 61% of malaria vaccine related patents are held by companies, 18% are available to the organization, and another 20% are available for public licensing. Another example of the intersection between public health and law.

Phase III malaria vaccine: don't count your eggs before they hatch

Two events prompted this post. First, several people have asked me if the malaria vaccine they heard about in the news will eliminate malaria. Second, the GSK CEO Andrew Witty discussed pricing strategies (5% profit above the yet unknown production costs) for this vaccine, called RTS,S, at a recent talk. Wait – pricing? We don’t even know how well the vaccine works! The press touts RTS,S as the world’s most advanced malaria vaccine. This is true in someways, it is in phase III trials which is the stage immediately preceding licensure and market sales. In and of itself this is a terrific achievement. However, advanced does not equal effective, and effective does not equal useful. Concerns about vaccine storage, dosing, delivery, and cost still remain.

The available RTS,S phase II results (previously discussed here) were far from spectacular, but efficacy was not the main endpoint of these trials. At that stage the investigators were focused on other aspects of a vaccine such as safety, dose finding, and immune response. The larger phase III study should answer the question of efficacy, but which efficacy are we talking about? Is it the efficacy in reducing all clinical malaria vs severe manifestations vs parasitemia or in children vs adults or for the first vs the fifth year after the receipt of the vaccine? Likely several different endpoints will be presented, and there will be disagreements about which one is meaningful for a particular country. If I were a betting man my guess is poor efficacy and low utility for public health, but I hope I’m wrong.

On a related note – will GSK receive a priority review voucher if RTS,S is licensed? The priority review voucher program was created in 2007 as an market-based incentive for companies to develop drugs and vaccines for neglected diseases. It allows a company to decrease the standard FDA review time, by 6-12 months, for another treatment of their choice. The economic value from the accelerated approval of a blockbuster drug is estimated at $100-500 million. Could the prospect of a voucher influence GSK’s decision to seek FDA approval? There is also the issue of the GSK-owned novel adjuvant (an immune response booster) used with RTS,S. What is the licensing process for adjuvants? I suspect that if an adjuvant has been used in a licensed vaccine, it can then be sold for use in any existing or new vaccine. Or at the least other companies would be more likely to risk using that adjuvant during vaccine development. If so, GSK may have another incentive to license RTS,S. From the talk of their CEO they already seem certain that a vaccine of any form will be pushed through the FDA.

PS GSK’s contribution and committment to the malaria vaccine began in 1987 and is commendable. Other contributors should also be noted. The Walter Reed Research Institute (run by the US Army) conducted much of the key early research. The Gates Foundation, through their Malaria Vaccine Initiative, has funded much of the vaccine’s development costs since 2001.

PPS The first voucher granted under the priority review program was for malaria. Novartis received one for its antimalarial drug Co-artem (artemether+lumefantrine). In this case the drug was not novel, available for almost a decade now, but was only recently licensed in the US making it eligible.

Malaria vaccine and more at Gooz News

I accidentally stumbled across the site Gooz News a year ago. Gooz News is the blog of longtime writer and reporter Merrill Goozner.  It was a fortuitous find of some rather interesting malaria thoughts (in both the actual posts as well as reader comments) that I have not seen elsewhere – particularly those which provided insight into the personal and policy disputes surrounding the popular topic of malaria vaccines.

Here are my favorites:

  1. NY Times article on the clash of science egos over rival malaria vaccines
  2. Comments on GSK credit for the advancement of a malaria vaccine
  3. The malaria vaccine and Dr Ruth Nussenzweig of New York University
  4. FDA priority review “prize” vouchers and the RTS,S vaccine
  5. Interview with Dr Francois Nosten of the Thai-Burma border Shoklo malaria unit

NEJM malaria articles and duration of protection for the RTS,S malaria vaccine

The latest issue of the New England Journal of Medicine contains a large set of malaria articles  including results from the RTS,S vaccine phase 2 trials. RTS,S is the malaria vaccine furthest along in the development pipeline and is managed by a public-private partnership led by GlaxoSmithKline and the PATH Malaria Vaccine Initiative (the early research was a GSK and Walter Reed collaboration). In order to prevent infections, the vaccine targets the Plasmodium falciparum circumsporozoite protein which is expressed by the infectious stage of the parasite released from mosquito bites. The first trials of RTS,S conducted in children in The Gambia reported 30 percent efficacy in reducing clinical malaria over a period of 6 months though the range of this estimated effect was between 11 and 45 percent.

In this latest study RTS,S decreased malaria cases by 58 percent (range 35-73) in children of ages 5-17 months from sites in Kenya and Tanzania. Key differences in this study included the use of a different adjuvant (administered alongside a vaccine target to boost immune response) and a younger population (in which the previous trial was more efficacious). The trial was underpowered due to a lower than expected malaria incidence in both study arms (though it is unclear why exactly, cost comes to mind, the follow-up period could not have been extended). A longer duration of follow-up may have also shed light on the duration of protection for the vaccine.  What we know so far is that between the 3 month and the next followup (varies from 4.5-10m), circulating antibody against the target protein decreased by roughly an order of magnitude. However, the authors could not find any association between antibody titers and protection. I suspect there is some association which would be evident with more cases and a further decrease in antibody concentrations.

Duration of protection will be a key determinant for the vaccine’s utility. If the length of protection is limited, a 3 dose schedule can not be easily implemented at regular intervals, regardless of vaccine cost. Assuming RTS,S will primarily target infants, a possible delivery mechanism is through the staple Expanded Program on Immunization where the 3 dose schedule can be integrated with similar vaccines.  Is EPI delivery enough for protection through childhood? Will there be a rebound effect after immunity wanes? Many questions await, but looks like we will have to wait for phase 3 trial results to know the full story.

Resurrecting the past to create a new malaria vaccine

I should begin with a disclaimer – I’m not a malaria vaccine researcher. The idea I’m proposing may be a dead end, or possess some fatal flow unknown to me. Still, from what I do know, it seems to make a lot of sense. I came to this idea after looking into older research regarding the epidemiology of gametocytes (the sexual stage of malaria parasites which is transmitted to mosquitoes). Some of the jargon below is a bit technical, but the basic idea is to use whole parasite stages to induce transmission blocking immunity (would not protect the individual but prevents the subsequent transmission of the infection). I have neither the expertise in this area nor the time to pursue the research – but here it is out in the open so someone might take it up and run with it:

An effective malaria vaccine remains elusive after decades of research. Current vaccine candidates demonstrate either limited protection and/or limited duration of protection. The contemporary paradigm of vaccine development using subunits has proven largely unsuccessful and points to the need for a new strategy – or perhaps an old one. “Crude vaccines” using whole cell approaches might be necessary to provide sufficient and robust protection against the parasite. In fact, the candidate vaccine with the best efficacy (albeit in a small sample) is the irradiated sporozoite vaccine being developed by Sanaria, Inc. However, this approach is expensive and will likely only provide a limited duration of protection. Another possible whole cell approach is the use of killed gametes. This idea has several merits. First, gametes are not part of the human stage of the parasite life cycle and therefore their antigens are under limited host selection pressure. Second, a whole cell vaccine induces broader immunity against multiple antigens making immune evasion by the parasite less likely. Third, gametocytes can be cultured in vitro which reduces the cost and complexity of creating vaccine relative to harvesting sporozoites from mosquitoes. Finally, several studies from the late 1970s showed near 100% transmission blocking protection in several animal models.

Species Animal model TB Efficacy (%) Dose (weeks given) Year Ref
P.gallinaceum Chicken 100 10^5 (5) 1976 1
99.9 10^5 (4)
96.2 10^5 (3)
P.gallinaceum Chicken 100 2.7^5 (3) 1976 2
P.knowlesi Rhesus monkey 100 10^7 + FCA (1) 1978 3
99.9 10^6 + FCA (2)
96.3 10^5 + FCA (1)
P.yoelli Mouse 100 2^8 + FCA (3) 1979 4

Why was such a promising approach abandoned?
A whole gamete vaccine was not furthered developed in humans because gametocyte yields from culture were low and the process was labor intensive (making obtaining the necessary doses very expensive) – if this could be overcome it would be a different matter. Also, safety concerns existed as parasites were grown in human blood. With the advent of powerful new molecular biology techniques, it was thought a subunit approach using gamete surface antigens would overcome the aforementioned challenges. Unfortunately, the subunit results have not proved as efficacious as whole gamete preparations.

Can we economically and safely produce a whole gamete vaccine?
Safety remains a challenge but if Sanaria, Inc can use blood fed mosquitoes to produce a live vaccine under GMP/FDA approval, then this obstacle may be overcome. In 2007, Fivelman et al. (5) reported an improved method for producing P.falciparum gametocytes in vitro through which one can reliably obtain 50 million stage V gametocytes from 100mL of culture. How many doses could this provide? Well, a key unknown exists: how many gametes are needed for an inoculating dose in humans? In any case this can be determined. The production process is where innovation needs to happen. An industrial culture system, finding the biochemical “signal” to induce gametocytogenesis, etc could be possibilities. To paraphrase a communication I had with one of the original researchers – the gametes worked as transmission blocking immunogens, anyone who could solve the problem of gamete mass production would have a great resource on their hands. In the end, a broad portfolio of vaccine development approaches will provide the best chance for producing a deployable vaccine. A whole gamete vaccine should be considered one key approach.

References
1. Gwadz, RW. 1976. Malaria: Successful immunization against the sexual stages of Plasmodium gallinaceum. Science 193, 1150-1151.
2. Carter, R., Chen, DH. 1976. Malaria transmission blocked by immunization with gametes of the malaria parasite. Nature, 263, 57-60.
3. Gwadz RW, Green I. Malaria immunization in Rhesus monkeys. A vaccine effective against both the sexual and asexual stages of Plasmodium knowlesi. J Exp Med. 1978 Nov 1; 148(5):1311-23.
4. Mendis et al. Immunization against gametes and asexual stages of a rodent malaria parasite. Nature. Vol 277, Feb 1979, 389-391.
5. Quivelman et al. Improved synchronous production of Plasmodium falciparum gametocytes in vitro. Molecular and Biochemical Parasitology. 154 (2007) 119–123
6. Malaria transmission blocking vaccines: an ideal public good. UNDP/World Bank/WHO/TDR. 2000.


Archives