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   bring you up to speed as of Tuesday Date: April 2, 2020 at 10:12:04 AM EDT To: Stewart Simonson Ce: Richard Hatchett cloud.com> Please treat as confidential. We have moved further. You will get an email re tomorrow's call - 12:30 Eastern. Excellent to talk with you as always. Will be even better working with you.* Richard * Especially if you do most of the work. Richard Danzig 3670 Upton St. NW Washington DC 20008 som Draft -- Not for Further Circulation Without Author's Approval A Six Month "Wartime" Vaccine Program v2 (March 29, 2019) Contact: Richard Danzig -- @email.com A vaccine is the single most important tool now missing in our fight against the corona virus. As many as 100! separate efforts are proceeding with unprecedented speed and resources to develop one or more vaccines. Though in the recent past it has taken at least a decade to move from conception to widespread distribution, these efforts are on an ambitious trajectory to produce a vaccine in 12-18 months. This paper proposes that a previously unrealistic goal of six months should be pursued and this can be done with justifiable risk. Peacetime constraints inhibited the 12-18 month plan from being accelerated further. A wartime effort can move twice as fast by embracing three innovations: e previously unthinkable government support in the form of underwriting costs, indemnification, maximum speed FDA review, acceptance of additional clinical and manufacturing risk appropriate to the enormous benefit, engagement of reluctant actors, and, if necessary, use of the Defense Production Act; e evaluation by a cohort study or human challenge trials rather than traditional clinical trials; e identification, funding and preparation of manufacturing assets before trials demonstrate success. These ideas have been vetted in discussion with leaders in the vaccine industry. This path can get us there if an overarching strategic plan is developed immediately, government actors embrace it, and initial actions are taken in the first half of April. The reward warrants the effort: wide availability of an effective vaccine in October could invaluably protect health care workers and other essential personnel, would greatly diminish a second cold weather wave of COV-19, permit economic recovery by assuring immunity to workers and consumers who receive it, and, through sharing globally, create immense goodwill and respect for America. A meeting will be held on March 31 at 8am California time to assess these ideas and no doubt to develop others that would contribute to a six-month vaccine. The agenda for a two and a half-hour meeting is: I. 20 minutes: brief general reactions, including expressions of enthusiasm and skepticism. Il. 60 minutes: participants construct the basics of a six-month plan, identifying the major initiatives that would need to occur to make the plan viable. This discussion will proceed without respect to whether participants are persuaded such a plan is likely to succeed. Ill. 30 minutes: discussion of whether participants view the plan as plausible enough to be worth the opportunity costs (distraction, etc.) and risks it will entail. IV. 40 minutes: If the plan is considered to be worth further effort, the group will discuss how to progress, including engagement of the US, European, India, and the PRC. Attachment 1 provides a Q&A on some key points about the plan along with footnotes pointing to some relevant reading. [Footnote not provided in this draft.] Attachment 2 lists those with whom the plan has been discussed. It does not imply endorsement. An asterisk indicates those who should be invited to the planned teleconference. It further lists a small number of others are proposed for invitation to the teleconference. Suggestions are welcome for others who might be especially important contributors. This meeting will not involve government participants after this first meeting. One question to be discussed is also when and how to engage governments Attachment 1 1. Isn't it very possible that present initiatives will not yield a good vaccine candidate in which case this strategy will not be rewarding? Yes. Decades after starting the search for an AIDS vaccine, we have not secured one. This strategy does not increase the odds of discovering a vaccine, it merely --- but if successful hugely beneficially --- accelerates the availability of that vaccine if it is discovered. 2. How substantial is the likelihood that mutations in Covid-19 will undercut the utility of a vaccine? That is distinctly possible, but most assessments have concluded that the virus is particularly stable, suggesting that immunity from infection or vaccine is likely to be long-lasting. The possibility of mutation argues for the six-month strategy. A longer period between development and distribution exposes us to greater risks from mutation. 3. What is the six-month goal? To have production at the level of tens of millions of doses per week by October 15, rapidly ramping up to hundreds of millions of doses per week using multiple facilities. 4. Can we put in place production capabilities without knowing which of a number of vaccines might establish their value in as yet uncompleted clinical trials? An RNA vaccine is in a class by itself in both its challenges and its potential. It needs to be addressed separately. Putting that vaccine aside for purposes of this discussion, modern front-end production equipment (vessels, etc.) has high fungibility between the three main forms of production: bacteria, mammalian cells and yeast. Requirements for GMP can in the main be met in advance, particularly if regulators participate in real time rather than review afterwards. Purification requirements are more varied. Fill/finish is relatively straightforward (though there is a risk that capacity could become limiting). A critical first step would be to survey the CMC (chemical, manufacturing and control) executives at the enterprises now investigating vaccine candidates to ascertain their intended mode of manufacture. Manufacturing plans could be made accordingly, with a great deal initiated immediately. Drug companies frequently build production capability before they have an approved product. How is this different? The principle is the same and the precedent is instructive. But this effort would be unprecedented in scale, scope and timing. The scale required is a production capacity for two to three hundred million doses for just the United States and more than two to three billion doses globally. Moreover, a drug company knows the specific products and processes for which it is building. This effort will have to prepare for manufacture of at least the leading 10 or so candidates and perhaps for many more. Finally, to meet a six-month target, investments will have to be made much earlier in the development cycle than is customary for companies. Can production capacity be found or created at the scale required? Some can be created and for an RNA vaccine an entirely new infrastructure would be required. For other types of vaccine, existing infrastructure would have to be reallocated. Some unused capability is readily identifiable. A majority of capacity, however, is likely to come from reallocation of existing facilities from a significant number of companies. Reallocation requires planning and discussion about financial costs and risks (e.g., if flu vaccine capabilities were reallocated to COVID-19). CEPI (Richard Hatchett) has pointed out that early recognition of potential reallocation demands could have the benefit of stimulating some present product to 24/7 production, thereby softening the effects of later reallocation. Discussion and planning is also necessary to establish a regime for sharing IP, financial reward, etc. and for standardizing production. It seems evident, however, that the capacity is there. Is it possible to assess the safety and efficacy of a vaccine candidate within six months? It is possible, though not by any means certain. Meeting that target might involve a month for determining a compound and manufacturing it in small quantities for initial trials; two months for initial trials (perhaps a combined Phase 1 and Phase 2) titrating the compound by administering it in varying doses and analyzing blood serum results; and three months for a cohort study or challenge study in lieu of a typical Phase 3 trial. The resulting vaccine might only be approved for certain populations pending a bridge study

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