莫德納 (MRNA) 2021 Q4 法說會逐字稿

Good morning. My name is Kevin, and I'll be the operator today. Welcome to Moderna's Fourth Quarter and Full Year 2021 Earnings Call. (Operator Instructions) Please be advised that this call is being recorded.

早上好。我叫凱文，今天我將擔任接線員。歡迎來到 Moderna 的 2021 年第四季度和全年財報電話會議。 （操作員說明）請注意，此通話正在錄音中。

At this time, I'd like to turn the call over to Lavina Talukdar, Head of Investor Relations at Moderna. Please proceed.

此時，我想將電話轉給 Moderna 投資者關係主管 Lavina Talukdar。請繼續。

Thank you, Kevin. Good morning, everyone, and thank you for joining us on today's call to discuss Moderna's fourth quarter and full year 2021 financial results and business update. You can access the press release we issued this morning as well as the slides that we'll be reviewing by going to the Investors section of our website. On today's call are Stephane Bancel, our Chief Executive Officer; David Meline, our Chief Financial Officer; Stephen Hoge, our President; and Paul Burton, our Chief Medical Officer.

謝謝你，凱文。大家早上好，感謝您加入我們今天的電話會議，討論 Moderna 的第四季度和 2021 年全年財務業績和業務更新。您可以訪問我們網站的“投資者”部分，訪問我們今天上午發布的新聞稿以及我們將審查的幻燈片。今天的電話是我們的首席執行官 Stephane Bancel；我們的首席財務官 David Meline；我們的總裁斯蒂芬·霍格；和我們的首席醫療官 Paul Burton。

Before we begin, please note that this conference call will include forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Please see Slide 2 of the accompanying presentation and our SEC filings for important risk factors that could cause our actual performance and results to differ materially from those expressed or implied in these forward-looking statements.

在我們開始之前，請注意，本次電話會議將包括根據 1995 年《私人證券訴訟改革法案》的安全港條款做出的前瞻性陳述。請參閱隨附演示文稿的幻燈片 2 和我們提交給 SEC 的重要風險因素可能導致我們的實際業績和結果與這些前瞻性陳述中明示或暗示的內容存在重大差異。

With that, I will turn over the call to Stephane.

有了這個，我會把電話轉給斯蒂芬。

Thank you, Lavina. Good morning or good afternoon, everyone. Welcome to our Q4 2021 conference call.

謝謝你，拉維娜。大家早上好或下午好。歡迎參加我們的 2021 年第四季度電話會議。

Today, I will start by a quick business review of fiscal year '21 before Paul walks you through some real-world evidence later. Stephen will then review our clinical programs before David presents our financial results. I will then come back to close, to share some thoughts about where we are heading.

今天，我將從對 21 財年的快速業務回顧開始，然後保羅將帶您了解一些真實世界的證據。然後，斯蒂芬將在大衛介紹我們的財務結果之前審查我們的臨床項目。然後我會回來結束，分享一些關於我們前進方向的想法。

We are pleased to report today $18.5 billion of revenues for fiscal year 2021 and a GAAP net income of $12.2 billion, translating into a GAAP diluted earnings per share of $28.29 billion, with a cash balance at the end of the year of $17.6 billion. We announced this morning that we have completed our August 2021 $1 billion share buyback plan, which reduced our average share count during the fourth quarter for the first time in the company history.

今天，我們很高興地報告 2021 財年的收入為 185 億美元，GAAP 淨收入為 122 億美元，按 GAAP 計算的攤薄後每股收益為 282.9 億美元，年底現金餘額為 176 億美元。我們今天早上宣布，我們已經完成了 2021 年 8 月的 10 億美元股票回購計劃，這在公司歷史上首次減少了第四季度的平均股票數量。

I am very proud of our team's ability to advance as well as expand with new programs our development pipeline. In respiratory vaccines, for COVID, as you know, we received full BLA approval from the U.S. FDA for Spikevax. With authorization for 12 to 17 years old in key markets globally, we are running a 50-microgram dose study in the U.S. for adolescents following discussions with the FDA. We are pleased to report that we have also started to receive authorization for children aged -- 6 to 11 years of age, beginning in Australia last week, with more countries expected in the days and weeks to come.

我為我們的團隊能夠通過新程序推進和擴展我們的開發管道而感到非常自豪。如您所知，在呼吸道疫苗方面，對於 COVID，我們獲得了美國 FDA 對 Spikevax 的全面 BLA 批准。獲得全球主要市場 12 至 17 歲兒童的授權後，我們正在與 FDA 討論後在美國為青少年進行 50 微克劑量研究。我們很高興地報告，我們也開始獲得 6 至 11 歲兒童的授權，從上週開始在澳大利亞，預計在未來幾天和幾週內將有更多國家。

We also dosed our first participants in our Omicron-specific vaccine trial, mRNA-1273.529. And today, we're announcing that we plan to bring mRNA-1273.214, a bivalent vaccine combining the wild-type vaccine mRNA1273 and the Omicron vaccine mRNA1273.529 into one single dose booster, into the clinic with total mass of 50 micrograms. We are very excited that now RSV is in Phase III. This is our third vaccine starting the Phase III. And for flu, we are waiting the Phase II data for mRNA1010. As soon as we have them, we will pick a dose and will initiate our Phase III for flu and we will start our Phase I for COVID plus flu program, mRNA1273.

我們還為我們的 Omicron 特異性疫苗試驗中的第一批參與者 mRNA-1273.529 給藥。今天，我們宣布計劃將 mRNA-1273.214（一種將野生型疫苗 mRNA1273 和 Omicron 疫苗 mRNA1273.529 組合成單劑量加強劑的二價疫苗）帶入臨床，總質量為 50 微克。我們很高興現在 RSV 處於第三階段。這是我們開始第三階段的第三個疫苗。對於流感，我們正在等待 mRNA1010 的 II 期數據。一旦我們有了它們，我們將選擇一個劑量，並將啟動我們的流感 III 期，我們將開始我們的 COVID 加流感計劃 mRNA1273 的 I 期。

For latent viruses, CMV is enrolling in Phase III, EBV and HIV are now in Phase I. And we are very excited to announce last week that we are adding 2 new latent virus programs to our development pipeline, one vaccine against HSV and one vaccine against VZV. More latent viruses vaccines are in the works in our labs.

對於潛伏病毒，CMV 正在進入 III 期，EBV 和 HIV 現在處於 I 期。上週我們非常高興地宣布，我們將在我們的開發管道中添加 2 個新的潛伏病毒項目，一種針對 HSV 的疫苗和一種疫苗反對 VZV。我們的實驗室正在研製更多潛伏病毒疫苗。

In therapeutics, PA and MMA are in the clinic, dosing and recruiting more patients. We announced a new checkpoint cancer vaccine, mRNA-4359. And Merck has informed us that they are returning the rights to the KRAS vaccine while evaluating future steps for this program.

在治療方面，PA 和 MMA 正在臨床中，為更多患者給藥和招募。我們宣布了一種新的檢查點癌症疫苗 mRNA-4359。默克公司已告知我們，他們將在評估該計劃的未來步驟時歸還 KRAS 疫苗的權利。

The company continues to expand at a rapid pace. We now have one approved medicine; 2 in Phase III, RSV and CMV; and 5 in Phase II, for a total of 44 programs. We are deploying capital to accelerate and expand the pipeline. The company now has 3,000 team members across the world with a great culture and 11 commercial subsidiaries across Americas, Europe and Asia Pacific. Our $17 billion cash balance at the end of the year is enabling us to scale across research, development, manufacturing, commercial and G&A.

公司繼續快速擴張。我們現在有一種獲批的藥物； 2 在 III 期，RSV 和 CMV；第二階段5個，共44個項目。我們正在部署資金以加速和擴大管道。該公司現在在全球擁有 3,000 名團隊成員，擁有良好的文化，並在美洲、歐洲和亞太地區擁有 11 家商業子公司。到年底，我們 170 億美元的現金餘額使我們能夠擴展研究、開發、製造、商業和 G&A。

With this, let me now turn to Paul.

有了這個，現在讓我轉向保羅。

Thank you, Stephane, and hello, everyone. It is almost exactly 3 months ago that we first heard about the [Omicron variant]. And today, we look back on 3 months that have seen millions of new cases of COVID-19 infection worldwide due to Omicron and a death toll that turned out to be almost 20% higher than that seen during the Delta wave. It is clear that SARS-CoV-2 is a virus capable of making very large evolutionary leaps in its structure and function. And while we are hopeful that we are about to enter a period of relative stability in the Northern Hemisphere, we believe firmly that a vaccine booster dose will be required for the fall of 2022 to provide ongoing protection against this virus.

謝謝你，斯蒂芬，大家好。我們第一次聽說 [Omicron 變體] 幾乎是 3 個月前。今天，我們回顧過去 3 個月，由於 Omicron 導致全球數百萬新的 COVID-19 感染病例，死亡人數比 Delta 浪潮期間高出近 20%。很明顯，SARS-CoV-2 是一種能夠在其結構和功能上進行非常大的進化飛躍的病毒。儘管我們希望北半球即將進入相對穩定的時期，但我們堅信，2022 年秋季將需要加強疫苗劑量，以提供針對這種病毒的持續保護。

We have seen measures taken by the United Kingdom recently to offer an additional booster dose to those at higher risk. And we believe such measures will become more widespread with governments looking to protect their populations from disease later this year and support their health care systems. As always, a huge note of appreciation to the frontline workers, the health care workers who have continued to immunize us and protect us during this pandemic. Their tireless work has saved millions of lives worldwide.

我們看到英國最近採取了措施，為高危人群提供額外的加強劑量。我們相信，隨著政府希望在今年晚些時候保護其人民免受疾病侵害並支持其醫療保健系統，此類措施將變得更加普遍。與往常一樣，非常感謝前線工作人員，在這場大流行期間繼續為我們免疫和保護我們的醫護人員。他們的不懈努力挽救了全球數百萬人的生命。

I'm going to review some data today that underpins why we believe an additional booster shot will be required certainly by the fall of 2022. First, let me share with you some data from a study of almost 440,000 individuals in the United States Veterans Administration database looking at the effectiveness of mRNA-1273, Spikevax, used in the primary series vaccination setting. As we know, the mRNA vaccines are extremely safe and effective, and the data here show the exceptional effectiveness of mRNA-1273.

今天我將回顧一些數據，這些數據支持我們為什麼認為到 2022 年秋季肯定需要額外的加強注射。首先，讓我與你分享一些來自美國退伍軍人管理局近 440,000 人的研究的數據數據庫查看用於初級系列疫苗接種設置的 mRNA-1273，Spikevax 的有效性。眾所周知，mRNA疫苗非常安全有效，這裡的數據顯示了mRNA-1273的非凡功效。

In this well-powered and prospectively designed comparative effectiveness study, mRNA-1273 significantly reduced the risk of COVID-19 infection and hospitalization compared to BNT162b2. These data are reassuring and continue to underpin the strong global confidence that governments, health care systems and individuals have in mRNA COVID-19 vaccines and mRNA-1273. Indeed, an example of that is the very recent announcement by the CDC at British Columbia for the preferential use of the Moderna vaccine in anyone over 12 years of age living with the immunocompromised.

在這項功能強大且前瞻性設計的比較有效性研究中，與 BNT162b2 相比，mRNA-1273 顯著降低了 COVID-19 感染和住院的風險。這些數據令人放心，並繼續鞏固全球政府、醫療保健系統和個人對 mRNA COVID-19 疫苗和 mRNA-1273 的強大信心。事實上，不列顛哥倫比亞省疾病預防控制中心最近宣布，12 歲以上患有免疫功能低下的人優先使用 Moderna 疫苗就是一個例子。

A similar pattern of results are seen from real-world effectiveness studies in the United Kingdom. The graphs I'm going to show you here come from the United Kingdom Health Security Agency, looking at the effect of either the Pfizer-BioNTech or Moderna vaccines and their vaccine effectiveness against hospitalization. First, let me show you the results in people who for their primary vaccination received the Pfizer-BioNTech vaccine and were then boosted with either the Pfizer-BioNTech vaccine or the Moderna vaccine. We see retained protection against the Delta variant of concern in the field squares but we see waning of effect in the field circles against Omicron.

從英國的實際有效性研究中可以看到類似的結果模式。我將在此處向您展示的圖表來自英國衛生安全局，研究了輝瑞-BioNTech 或 Moderna 疫苗的效果及其對住院的疫苗有效性。首先，讓我向您展示初次接種輝瑞-BioNTech 疫苗，然後使用輝瑞-BioNTech 疫苗或 Moderna 疫苗加強免疫的人的結果。我們看到在場方塊中保留了對關注的 Delta 變體的保護，但我們看到場圈對 Omicron 的影響減弱。

The same is true though more pronounced on the next part of this graph. And here, you see individuals who received as their primary vaccine the AstraZeneca vaccine. Again, in this very large real-world assessment, we can see that mRNA-1273 provides protection against hospitalization due to both Delta but to a lesser extent, Omicron infection.

雖然在該圖的下一部分更為明顯，但情況也是如此。在這裡，您會看到接受阿斯利康疫苗作為主要疫苗的個人。同樣，在這個非常大的真實世界評估中，我們可以看到 mRNA-1273 可以防止因 Delta 而住院，但在較小程度上，Omicron 感染。

Of note, we do see waning of protection over time against hospitalization due to Omicron infection, and this fits with the profound immune invasion we know to be the case with Omicron. But it is also a driver of our belief that not only will a booster vaccination be required later in 2022 but also a booster will be required that protects against both the Delta and Omicron variants of concern, as Stephane announced earlier. This is because Delta, as we know, is associated with strong pathogenicity and Omicron, as we have seen, due to its transmissibility and infectivity, is also associated with substantial morbidity and strain on health care systems through sheer bulk of cases, hence protection against both Delta and Omicron may well be necessary in the next booster vaccination.

值得注意的是，隨著時間的推移，我們確實看到 Omicron 感染對住院的保護作用減弱，這與我們知道的 Omicron 的嚴重免疫入侵相吻合。但這也促使我們相信，正如 Stephane 早些時候宣布的那樣，不僅需要在 2022 年晚些時候進行加強疫苗接種，而且還需要加強疫苗來預防所關注的 Delta 和 Omicron 變種。這是因為眾所周知，Delta 與強致病性有關，而 Omicron，正如我們所見，由於它的傳播性和傳染性，還與大量病例對醫療保健系統的嚴重發病率和壓力有關，因此可以防止Delta 和 Omicron 很可能在下一次加強疫苗接種中都是必需的。

On Slide 10, we see data directly explaining the clinical phenomenon I just showed you. These data come from one of our previously conducted clinical studies. Sera from individuals immunized and boosted with mRNA-1273 is able to substantially neutralize the ancestral SARS-CoV-2 virus, D614G, shown here in black, but to a lesser extent, Omicron, shown in red. And this is particularly true by 6 months following booster administration. Again, it is these data, coupled with the real-world effectiveness data that I just showed you, that leads us to believe an additional booster dose will be needed later in 2022, providing protection against both Delta and Omicron variants of concern.

在幻燈片 10 上，我們看到的數據直接解釋了我剛剛向您展示的臨床現象。這些數據來自我們之前進行的一項臨床研究。來自用 mRNA-1273 免疫和加強的個體的血清能夠基本上中和祖先的 SARS-CoV-2 病毒 D614G，這里以黑色顯示，但在較小程度上，Omicron，以紅色顯示。在加強給藥後 6 個月尤其如此。同樣，正是這些數據，再加上我剛剛向您展示的真實世界有效性數據，使我們相信在 2022 年晚些時候將需要額外的加強劑量，以提供針對關注的 Delta 和 Omicron 變體的保護。

You can see this point made clearly again in Slide 11, where we estimate the duration of protection against either the ancestral D614G strain or against Omicron. With lower starting titers, protection against Omicron wanes and forwards to levels that would begin to allow breakthrough infection to occur due to Omicron around 9 months after boosting. As leaders in mRNA vaccines and COVID-19 disease, we will continue to monitor this carefully along with other emerging variants and continue to do whatever we can to provide people with a safe and highly effective vaccine booster for 2022 and years to come. We announced in January that we were able to go from identification of Omicron to testing of a new vaccine in humans in just 2 months. That is a remarkable testament to the Moderna mRNA platform and its utility.

您可以在幻燈片 11 中再次清楚地看到這一點，我們在其中估計了針對祖先 D614G 菌株或針對 Omicron 的保護持續時間。隨著較低的起始滴度，對 Omicron 的保護減弱並前進到將在加強後約 9 個月時開始允許由於 Omicron 發生突破性感染的水平。作為 mRNA 疫苗和 COVID-19 疾病的領導者，我們將繼續仔細監測這一點以及其他新出現的變種，並繼續盡我們所能為 2022 年和未來幾年的人們提供安全、高效的疫苗助推器。我們在一月份宣布，我們能夠在短短 2 個月內從 Omicron 的鑑定到在人體中測試一種新疫苗。這是對 Moderna mRNA 平台及其實用性的非凡證明。

Slide 12 will be familiar to many of you as we first presented this slide at our Vaccines Day in April 2021. The graph is an illustration of the different phases of the pandemic to endemic continuum and its effect as measured by morbidity or disease burden over time. The shape of the graph was adopted from what we knew about previous pandemics at the time and what we expected from the current pandemic, taking into consideration the increased levels of immunity that our immune systems collectively became familiarized with the SARS-CoV-2 virus, either through infection or vaccination. As the graph shows and with hindsight, it is easy to recognize that the very first wave of the pandemic when all of the world's population was naive to this virus caused the highest levels of morbidity and mortality. With each subsequent wave in mid-2021 with Delta and in late 2021 and early 2022 with Omicron, the morbidity observed from these waves tended to be less severe certainly relative to the first wave as our immune systems became more experienced at fighting the SARS-CoV-2 virus.

當我們在 2021 年 4 月的疫苗日首次展示這張幻燈片時，你們中的許多人都會熟悉幻燈片 12。該圖說明了從大流行到地方性連續體的不同階段及其影響，通過發病率或疾病負擔隨時間推移來衡量.圖表的形狀取自我們當時對先前大流行的了解以及我們對當前大流行的預期，考慮到我們的免疫系統共同熟悉 SARS-CoV-2 病毒的免疫力水平提高，通過感染或疫苗接種。正如圖表所示，事後看來，很容易認識到，當世界上所有人口都對這種病毒幼稚時，大流行的第一波就導致了最高水平的發病率和死亡率。隨著 2021 年年中 Delta 和 2021 年末和 2022 年初 Omicron 的每一波後續浪潮，隨著我們的免疫系統在對抗 SARS-CoV 方面變得更有經驗，從這些浪潮中觀察到的發病率肯定相對於第一波來說沒有那麼嚴重-2 病毒。

Beyond 2022, there still remains uncertainty. However, given what we know now of other pandemics like the 1918 influenza pandemic and more importantly, what we have observed with the SARS-COV-2 pandemic, we do believe that we are transitioning into an endemic phase, marked by a period of stability in case counts, hospitalizations and death at least in the Northern Hemisphere. We will continue to carefully monitor the situation in the Southern Hemisphere as winter approaches there on a background of continuing Delta and Omicron infection pressure, and we will work as quickly as possible to generate new specific booster vaccine data.

2022年之後，仍然存在不確定性。然而，鑑於我們現在對 1918 年流感大流行等其他大流行的了解，更重要的是，我們在 SARS-COV-2 大流行中觀察到的情況，我們確實相信我們正在過渡到一個以穩定期為標誌的流行階段至少在北半球，在病例數、住院人數和死亡人數方面。在 Delta 和 Omicron 感染壓力持續存在的背景下，隨著冬季臨近，我們將繼續仔細監測南半球的情況，我們將盡快生成新的特定加強疫苗數據。

In the endemic phase, the virus will continue to circulate but at rates that are static and more predictable. We continue to expect morbidity from the virus when it is endemic, and we believe, like other respiratory viruses, we will see a seasonal pattern of disease that emerge. But the good news is, because our immune system is now much more familiar with the virus, either through vaccination, infection or both, we do not expect that the majority of the population will be as susceptible to severe disease in the endemic phase as they were in the pandemic phase. Instead, as with other respiratory viruses, we believe protection from SARS-COV-2 will be critical for populations that are likely to be most susceptible to severe disease and high burden of disease. Providing the broadest protection possible will be a focus for us in the endemic phase, and we believe, as Stephane mentioned, multivalent vaccines against SARS-COV-2 and its variants will help achieve this.

在流行階段，病毒將繼續傳播，但傳播速度是靜態的且更可預測。我們繼續預計該病毒在流行時會導致發病率，並且我們相信，與其他呼吸道病毒一樣，我們將看到出現季節性疾病模式。但好消息是，由於我們的免疫系統現在對病毒更加熟悉，無論是通過疫苗接種、感染還是兩者兼而有之，我們預計大多數人在流行階段不會像他們一樣容易感染嚴重疾病。處於大流行階段。相反，與其他呼吸道病毒一樣，我們認為對 SARS-COV-2 的保護對於可能最容易感染嚴重疾病和高疾病負擔的人群至關重要。提供盡可能廣泛的保護將是我們在流行階段的重點，我們相信，正如斯蒂芬所說，針對 SARS-COV-2 及其變體的多價疫苗將有助於實現這一目標。

As I alluded to earlier, respiratory viruses cause significant disease annually and endemic coronaviruses are no exception to this. Slide 13 shows the incidence of community-acquired infections leading to hospitalizations in New York City during the 2018 to 2019 season prior to the SARS-CoV-2 pandemic. On the chart, you can see that other endemic human coronaviruses, in fact, cause the highest level of hospitalizations in individuals between 65 and 79 years of age and those 80 years and above, followed by RSV and influenza. Across OECD countries, the estimated impact from endemic human coronaviruses leads to over 1 million outpatient visits, 350,000 hospitalizations and 20,000 deaths in the over 65-year-old population annually.

正如我之前提到的，呼吸道病毒每年都會引起重大疾病，地方性冠狀病毒也不例外。幻燈片 13 顯示了 SARS-CoV-2 大流行之前的 2018 年至 2019 年期間紐約市社區獲得性感染導致住院的發生率。在圖表上，您可以看到其他地方性人類冠狀病毒實際上導致 65 至 79 歲和 80 歲及以上人群的住院率最高，其次是 RSV 和流感。在經合組織國家中，地方性人類冠狀病毒的估計影響每年導致超過 65 歲的人口超過 100 萬次門診就診、35 萬次住院和 2 萬例死亡。

We believe SARS-CoV-2 will follow a similar pattern of seasonal disease as other respiratory viruses do and will impact vulnerable populations. Protecting populations against SARS-CoV-2 will be critical in the months and years to come. And protecting against combinations of respiratory viruses such as SARS-CoV-2, flu and RSV with a single yearly shot will be central to our strategy. Stephen Hoge will shortly provide an update on our robust ongoing strategy to achieve that.

我們相信 SARS-CoV-2 將遵循與其他呼吸道病毒類似的季節性疾病模式，並將影響弱勢群體。在未來的幾個月和幾年中，保護人群免受 SARS-CoV-2 感染將至關重要。每年接種一次疫苗以預防 SARS-CoV-2、流感和 RSV 等呼吸道病毒的組合將是我們戰略的核心。斯蒂芬·霍格（Stephen Hoge）將很快提供有關我們實現這一目標的穩健持續戰略的最新信息。

So in summary, the available real-world data continue to show the remarkable effectiveness of mRNA-1273. Real-world data shows that a 50-microgram booster dose of mRNA-1273 provides protection against hospitalization caused by Omicron, but we note waning of antibody titers by 6 months post boosting. We believe that a fall 2022 booster will be needed globally. And as leaders in mRNA vaccines, we believe it is important to develop booster vaccines that will give us an opportunity to protect against Omicron and future variants as we continue our fight to help end this pandemic.

因此，總而言之，可用的真實世界數據繼續顯示 mRNA-1273 的顯著有效性。真實世界數據顯示，加強劑量的 50 微克 mRNA-1273 可防止因 Omicron 引起的住院，但我們注意到加強後 6 個月抗體滴度減弱。我們認為，全球將需要 2022 年秋季的助推器。作為 mRNA 疫苗的領導者，我們認為開發加強疫苗非常重要，這將使我們有機會在我們繼續努力幫助結束這一流行病的過程中預防 Omicron 和未來的變種。

I will now hand over to Dr. Stephen Hoge to provide further updates on this topic and the Moderna pipeline. Stephen?

我現在將移交給 Stephen Hoge 博士，以提供有關該主題和 Moderna 管道的進一步更新。斯蒂芬?

Thank you, Paul. Good morning and good afternoon, everyone. On Slide 16, I'd like to briefly summarize our COVID-19 booster development strategy for the endemic phase.

謝謝你，保羅。大家早上好，下午好。在幻燈片 16 上，我想簡要總結一下我們針對流行階段的 COVID-19 助推器開發策略。

As Paul covered, the strategic rationale for a seasonal booster has 3 parts. First, we think neutralizing titers will wane similar to the endemic human coronaviruses, as Paul just described. That decline in neutralizing titers will increase the risk of breakthrough hospitalization in those at higher risk, specifically including older adults and the immune compromised. We think the emergence of new variants of concern will also have the risk of accelerating waning and broadening the risk of breakthroughs to other populations.

正如保羅所說，季節性補充包的戰略原理包括 3 個部分。首先，正如保羅剛剛描述的那樣，我們認為中和滴度會像地方性人類冠狀病毒一樣減弱。中和滴度的下降將增加高風險人群的突破性住院風險，特別是包括老年人和免疫功能受損的人群。我們認為，關注的新變種的出現也將有加速減弱的風險，並將突破的風險擴大到其他人群。

So the desired features for our Northern Hemisphere fall and winter 2022 booster are described here. First, we'd like to improve the durability of protection for neutralizing antibodies against Omicron and Omicron mutations to at least 6 months that will provide full protection through the Northern Hemisphere fall/winter infection season. We'd like to retain the high and durable protection we've been seeing with a prototype vaccine against Delta and the ancestral strains. And third, we'd like to broaden cross-protective immunity to the extent possible to increase the potential for protection against a new emergent variant of concern, which could emerge perhaps from the Southern Hemisphere this midyear.

因此，此處描述了我們的北半球 2022 年秋冬助推器所需的功能。首先，我們希望將針對 Omicron 和 Omicron 突變的中和抗體的保護持久性提高到至少 6 個月，這將在整個北半球秋冬感染季節提供全面保護。我們希望保留我們已經看到的針對 Delta 和祖先菌株的原型疫苗所提供的高度和持久的保護。第三，我們希望盡可能擴大交叉保護免疫，以增加對新出現的關注變體的保護潛力，這種變體可能會在今年年中從南半球出現。

So on Slide 17, I'll quickly summarize our strategy for developing an updated booster for fall 2022. We are currently evaluating 3 different booster strategies in adults aged 18 plus. The first, as both Paul and Stephane have mentioned, is a bivalent booster vaccine made up of the prototype mRNA-1273 and an Omicron-specific mRNA-1273.529. This bivalent has been called 214. We are also evaluating, as we previously announced, an Omicron-specific booster, mRNA-1273.529. And of course, we will continue to evaluate our prototype booster, mRNA-1273, for which there is a large body of real-world evidence, as Paul just described.

因此，在幻燈片 17 上，我將快速總結我們為 2022 年秋季開發更新的助推器的策略。我們目前正在評估 18 歲以上成年人的 3 種不同的助推器策略。第一種，正如 Paul 和 Stephane 所提到的，是由原型 mRNA-1273 和 Omicron 特異性 mRNA-1273.529 組成的二價加強疫苗。這種二價化合物被稱為 214。正如我們之前宣布的，我們還在評估一種 Omicron 特異性增強劑 mRNA-1273.529。當然，我們將繼續評估我們的原型助推器 mRNA-1273，正如保羅剛剛描述的那樣，它有大量的現實證據。

We're evaluating these 3 different approaches across 2 studies in the United States and the United Kingdom, a Phase II study in the United States of approximately 750 participants and a 3,000-participant study in the United Kingdom. Both are looking at both bivalent and Omicron-specific boosters, and both will be looking at both third and fourth dose of those boosters. In the U.K. study, we will also be looking at heterologous boosting, including on the background of other mRNA vaccines and non-mRNA vaccines.

我們正在美國和英國的 2 項研究中評估這 3 種不同的方法，在美國進行的 II 期研究有大約 750 名參與者，在英國有 3,000 名參與者的研究。兩者都在研究二價和 Omicron 特異性增強劑，並且都將研究這些增強劑的第三劑和第四劑。在英國的研究中，我們還將研究異源加強免疫，包括在其他 mRNA 疫苗和非 mRNA 疫苗的背景下。

Now I'd like to take a moment on Slide 18 to provide some scientific insight to why we believe the bivalent vaccine booster for the fall of 2022 offers a potential advantage. Slide 18 includes data on some of our prior bivalent boosters, and this data -- this emerging data suggest to us that there may be an opportunity to improve durability against variants of concern while preserving activity against the ancestral variants. This data is based on one of our prior bivalents, mRNA1273.211 or 211 for short.

現在，我想在幻燈片 18 上花一點時間來提供一些科學見解，說明為什麼我們認為 2022 年秋季的二價疫苗增強劑具有潛在優勢。幻燈片 18 包括我們之前的一些二價助推器的數據，這些數據——這些新出現的數據向我們表明，可能有機會提高針對關注變體的持久性，同時保留針對祖先變體的活性。該數據基於我們先前的二價之一，簡稱 mRNA1273.211 或 211。

And 211, as you may recall, was based on the 1273 vaccine and the Beta variant of concern, which emerged approximately a year ago. When we compare over time how the 2 different booster strategies, our prototype booster on the left-hand column here, and our bivalent booster on the right-hand column here, do against the 2 different virus variants that were in the vaccine, you see an emergence of potential improvement in durability.

您可能還記得，211 是基於大約一年前出現的 1273 疫苗和備受關注的 Beta 變體。當我們隨著時間的推移比較 2 種不同的加強策略，我們在左側欄中的原型加強策略，以及我們在右側欄中的二價加強策略，如何對抗疫苗中的 2 種不同的病毒變體，你會看到耐久性的潛在改進的出現。

So first, to orient you to the slide. mRNA-1273 was given at 50 micrograms as a booster to those who had previously received 2 doses of mRNA-1273 vaccine. And on the top left panel, you'll see how -- the neutralizing titers or pseudovirus neutralizing titers against the ancestral strain of the virus, D614G virus, in our validated clinical assays. Underneath there, you'll see how those -- the pseudovirus neutralization titers against the Beta variant of concern in blue. And in the middle column, you'll contrast that with the bivalent 211 booster, which, in this case, included the Beta variant of concern, again, at the same dose level, 50 micrograms. Top right panel is the ancestral variant of concern -- the ancestral virus, D614G, and lower right is the Beta variant of concern or the B1.351.

因此，首先，讓您了解幻燈片。 mRNA-1273 的劑量為 50 微克，作為對之前接受過 2 劑 mRNA-1273 疫苗的人的增強劑。在左上角的面板上，您將看到在我們經過驗證的臨床試驗中，中和效價或假病毒中和效價對病毒祖先株 D614G 病毒的中和效價。在下面，你會看到那些——偽病毒中和效價如何對抗關注的藍色 Beta 變體。在中間一欄中，您將把它與二價 211 加強劑進行對比，在這種情況下，它包括關注的 Beta 變體，同樣劑量水平為 50 微克。右上圖是關注的祖先變體——祖先病毒 D614G，右下圖是關注的 Beta 變體或 B1.351。

Now as you'll note, comparing the performance against the ancestral D614G virus, both mRNA-1273 and the bivalent Beta-containing booster do a good job boosting neutralizing titers by day 29 after the booster. So 1 month post booster, neutralizing titers are approximately 1,800 for 1273 and 2,200 for the bivalent. And importantly, as we test the serum 6 months after booster, noted as day 181 here, you'll see that neutralizing titers remain high, approximately 1,000 in both boosters.

現在您將注意到，比較與祖先 D614G 病毒的性能，mRNA-1273 和含二價 Beta 的加強劑在加強劑後第 29 天可以很好地提高中和滴度。因此，加強後 1 個月，1273 的中和效價約為 1,800，二價的中和效價約為 2,200。重要的是，當我們在加強免疫後 6 個月測試血清時（此處標註為第 181 天），您會發現中和效價仍然很高，在兩次加強免疫中都約為 1,000。

Now the situation against the variant of concern, in this case, Beta, is slightly different. Again, both boosters increased neutralizing titers by day 29 1 month after booster to quite reasonable levels, approximately 1,000 in both cases. However, when you follow out 6 months, there is a difference in the neutralizing titers that emerges. And not surprisingly, the bivalent booster, which includes the Beta variant of concern, starts to see more durable neutralizing titers, 402, as noted here, as opposed to 154 for mRNA-1273.

現在，針對關注的變體（在本例中為 Beta）的情況略有不同。同樣，兩種加強劑都在加強劑後 1 個月的第 29 天將中和效價提高到相當合理的水平，在兩種情況下都約為 1,000。但是，當您隨訪 6 個月時，出現的中和滴度會有所不同。毫不奇怪，包括關注的 Beta 變體的二價增強劑開始看到更持久的中和滴度，如本文所述，402，而不是 mRNA-1273 的 154。

So in summary, 6 months after a 211 bivalent booster, the neutralizing titers against the Beta variant of concern appear to be more durable than with just a prototype booster. And the durability or the rate of decline for the Beta neutralizing titers more closely matches that seen for the ancestral virus following the bivalent 211 booster. Including the Beta variant of concern, therefore, appears to be improving the durability of neutralizing titers against that variant of concern.

因此，總而言之，在 211 二價增強劑 6 個月後，針對所關注的 Beta 變體的中和滴度似乎比僅使用原型增強劑更持久。並且 Beta 中和滴度的持久性或下降速度更接近於在二價 211 增強劑之後看到的祖先病毒。因此，包括關注的 Beta 變體似乎正在提高針對該關注變體的中和滴度的持久性。

Now on the next slide, Slide 19, we have that same data but now plotted as a function of time to help you visualize it a little more clearly. On the left-hand side, we're contrasting the mRNA-1273 booster as a black line against a bivalent Beta-containing booster in the red line. On the left-hand side, you're again looking at the ancestral D614G neutralizing titers. And as you can see, following a booster approximately 6 months after dose 2, neutralizing titers for both of the boosters, both bivalent and the prototype vaccine, increased significantly. And the data we have out to 6 months, if you project that forward as we do with the dotted lines, suggest that we will maintain quite high neutralizing titers, perhaps as long as 1 year.

現在在下一張幻燈片上，幻燈片 19，我們有相同的數據，但現在繪製為時間的函數，以幫助您更清楚地可視化它。在左側，我們將 mRNA-1273 增強劑作為黑線與紅線中含有二價 Beta 的增強劑進行對比。在左側，您再次看到了祖先的 D614G 中和滴度。正如您所看到的，在第 2 劑疫苗後大約 6 個月進行加強免疫後，二價疫苗和原型疫苗這兩種加強免疫的中和效價均顯著增加。我們擁有 6 個月的數據，如果你像我們用虛線那樣向前預測，表明我們將保持相當高的中和滴度，可能長達 1 年。

Now the situation on the right-hand side highlights, we think, the potential for improving durability with a bivalent vaccine. Again, here, the black line is mRNA-1273 and the red line is the bivalent Beta-containing booster at the same dose level. Now while both boosters increase neutralizing titers to approximately 1,000 within 1 month of boosting, what starts to emerge 6 months later is a different degree of durability in those neutralizing titers with the bivalent vaccine containing the Beta antigen doing slightly better, as you can see with the red line. And if you project that forward, it suggests that the bivalent vaccine neutralizing titers against the Beta variant of concern will remain quite high, perhaps as long as a year, whereas with the prototype vaccine, those neutralizing titers appear to be decaying more quickly, back towards baseline levels or pre-booster levels by approximately 8 to 9 months.

現在，我們認為右側的情況突出了使用二價疫苗提高耐用性的潛力。同樣，在這裡，黑線是 mRNA-1273，紅線是相同劑量水平的二價含 Beta 增強劑。現在，雖然兩種加強劑在加強後 1 個月內將中和效價提高到大約 1,000，但 6 個月後開始出現的是，這些中和效價的持久性程度不同，含有 Beta 抗原的二價疫苗表現稍好，如您所見紅線。如果你向前預測，它表明針對關注的 Beta 變體的二價疫苗中和滴度將保持相當高，可能長達一年，而對於原型疫苗，這些中和滴度似乎衰減得更快，返回大約 8 到 9 個月達到基線水平或加強前水平。

On Slide 20, just to quickly summarize therefore where we are on COVID-19 booster development for fall 2022. We believe that a seasonal booster will be necessary to prevent breakthrough diseases, including hospitalization in vulnerable populations. And we believe that the continued evolution of the virus is going to continue to put pressure on pre-existing immunity, whether that's naturally derived or vaccine provided.

在幻燈片 20 上，只是為了快速總結一下我們在 2022 年秋季 COVID-19 助推器開發方面的進展。我們認為，季節性助推器對於預防突破性疾病是必要的，包括弱勢人群的住院治療。而且我們相信，病毒的持續進化將繼續對預先存在的免疫力施加壓力，無論是天然來源的還是提供的疫苗。

We think the fall 2022 booster should reflect the diversity of circulating mutations that are out there in order -- and seek to achieve greater than 6 months of neutralizing titer durability to increase the potential for protection throughout the entire fall season; in this case, we think September through February. So Moderna is developing an Omicron-containing bivalent booster, based on data that we have from prior bivalent candidates that suggests that incorporating the variant of concern and those mutations from that variant of concern, has the potential to improve the durability against such variant of concern.

我們認為 2022 年秋季助推器應反映按順序排列的循環突變的多樣性——並尋求實現超過 6 個月的中和滴度持久性，以增加整個秋季的保護潛力；在這種情況下，我們認為從 9 月到 2 月。因此，Moderna 正在開發一種含有 Omicron 的二價增強劑，基於我們從之前的二價候選者那裡獲得的數據，這些數據表明，結合關注的變體和來自該關注的變體的那些突變，有可能提高針對這種關注變體的持久性.

Now moving to Slide 21, just quickly catching up on other developments in our COVID-19 vaccine. We have made progress in primary series and booster in adolescent and pediatric populations. So in adolescents first.

現在轉到幻燈片 21，只是快速趕上我們 COVID-19 疫苗的其他發展。我們在青少年和兒科人群的初級系列和加強免疫方面取得了進展。所以首先是青少年。

We've received regulatory approvals for Spikevax in Europe, United Kingdom, Australia, Canada and many other countries. In the U.S., we plan to submit an EUA for 100 micrograms of mRNA-1273 in adolescents that are immune compromised or at elevated risk of severe outcomes. And we're also evaluating the potential of a lower dose, 50 micrograms, as a primary series. And lastly, as has been noted previously, we're preparing to submit data for 50 micrograms as a booster dose in adolescents and 50 micrograms as the booster dose in adults as well, and that will include data on heterologous boosting.

我們已經在歐洲、英國、澳大利亞、加拿大和許多其他國家獲得了 Spikevax 的監管批准。在美國，我們計劃為免疫受損或嚴重後果風險升高的青少年提交 100 微克 mRNA-1273 的 EUA。我們還在評估較低劑量（50 微克）作為主要係列的潛力。最後，如前所述，我們正準備提交 50 微克作為青少年加強劑量和 50 微克作為成人加強劑量的數據，其中將包括異源加強的數據。

In pediatrics or the 6- to 11-year-old, we've received provisional approval for Spikevax in Australia and submitted to multiple other international regulatory agencies and expect authorization shortly. The U.S. submission is pending alignment with the United States FDA on the adolescent application, and we will also continue to evaluate lower doses, including a 25-microgram primary series dose.

在兒科或 6 至 11 歲的兒童中，我們已在澳大利亞獲得了 Spikevax 的臨時批准，並已提交給多個其他國際監管機構，預計很快就會獲得批准。美國提交的申請正在等待與美國 FDA 就青少年申請保持一致，我們還將繼續評估較低劑量，包括 25 微克的主要係列劑量。

Finally, in the youngest, 6 months to 5 years old pediatric population, we expect data on our 25-microgram 2-dose primary series in the first quarter. And pending that data, we'll plan to submit to regulators. We are also continuing to evaluate lower doses and the potential of a third dose in that population.

最後，在最年輕的 6 個月至 5 歲兒科人群中，我們預計第一季度的 25 微克 2 劑初級系列的數據。在這些數據之前，我們將計劃提交給監管機構。我們還在繼續評估該人群中較低劑量和第三劑的潛力。

Pivoting to the broader respiratory vaccine portfolio on Slide 22. Beyond COVID-19, we continue to make progress across all of our respiratory vaccines. As Stephane mentioned, our flu vaccine is fully enrolled with Phase II. And pending that data, we will prepare to move forward, which we still anticipate doing in 2022, into a Phase III study. We're also preparing to start a combination flu and COVID vaccine, which is currently in preclinical but we expect to start the Phase I study this year.

在幻燈片 22 上轉向更廣泛的呼吸道疫苗組合。除了 COVID-19，我們繼續在所有呼吸道疫苗方面取得進展。正如 Stephane 所說，我們的流感疫苗已完全進入 II 期。在獲得這些數據之前，我們將準備推進，我們仍預計在 2022 年進行的第三階段研究。我們還準備啟動流感和 COVID 聯合疫苗，該疫苗目前處於臨床前階段，但我們預計將在今年開始 I 期研究。

Our older adult RSV program has started its Phase III study portion, and that pivotal study is ongoing and enrolling. We have a pediatric RSV study which we will move forward in Phase I. We have also 2 different respiratory combination vaccines: first, the human metapneumovirus and parainfluenza virus 3 vaccine, which is in Phase Ib and is now fully enrolled; an RSV plus HMPV vaccine, which remains in preclinical development and we hope to start shortly.

我們的老年人 RSV 計劃已開始其 III 期研究部分，該關鍵研究正在進行中並正在招募中。我們有一項兒科 RSV 研究，我們將在 I 期推進。我們還有 2 種不同的呼吸道聯合疫苗：第一，人偏肺病毒和副流感病毒 3 疫苗，目前處於 Ib 期，現已全面註冊；一種 RSV 加 HMPV 疫苗，目前仍處於臨床前開發階段，我們希望盡快開始。

Moving now to latent and public health vaccines on Slide 23. As discussed, CMV continues to enroll in the Phase III CMVictory study. We have also moved forward 2 new latent virus vaccines in the clinical testing. Our EBV vaccine to prevent infectious mononucleosis is in Phase I, and our HIV -- our first HIV vaccine, mRNA-1644, is also in Phase I. We announced 2 new development candidates, which I'll cover briefly in the next couple of slides, against HSV and VZV. And our public health vaccines against Zika and Nipah continue to progress.

現在轉到幻燈片 23 上的潛伏和公共衛生疫苗。如上所述，CMV 繼續參加 III 期 CMVictory 研究。我們還在臨床試驗中推進了兩種新的潛伏病毒疫苗。我們預防傳染性單核細胞增多症的 EBV 疫苗處於 I 期，我們的 HIV（我們的第一個 HIV 疫苗 mRNA-1644）也處於 I 期。我們宣布了 2 個新的開發候選者，我將在接下來的幾篇文章中簡要介紹幻燈片，針對 HSV 和 VZV。我們針對寨卡病毒和尼帕病毒的公共衛生疫苗繼續取得進展。

Briefly, on Slide 24, I'd like to introduce our -- the first of our 2 new development candidates in the space. mRNA-1608 is our vaccine against herpes simplex virus 2. HSV-2 primarily infects the genitals and establishes lifelong latent infections within the sensory neurons. There's a significant burden of disease in developed markets, including approximately 18 million people who are HSV-positive -- HSV-2 positive in the United States. Globally, that represents about 5% of the population. Primary burden of disease is a reduction in quality of life from recurrent lesions.

簡而言之，在幻燈片 24 上，我想介紹我們的 - 我們在該領域的兩個新開發候選人中的第一個。 mRNA-1608 是我們針對單純皰疹病毒 2 的疫苗。HSV-2 主要感染生殖器並在感覺神經元內建立終身潛伏感染。發達市場的疾病負擔很重，其中包括大約 1800 萬 HSV 陽性（美國 HSV-2 陽性）的人。在全球範圍內，這約佔人口的 5%。疾病的主要負擔是複發性病變導致生活質量下降。

Our mRNA-1608 vaccine encodes antigens on the surface of the HSV virus and has been able to induce very strong immune responses, as illustrated in the figure to the right. Neutralizing titers in mice following an HSV-2 vaccine with mRNA-1608 are significantly above the levels seen in human sera from those who are seropositive. This gives us reason to believe that we will be able to provide a significant benefit with this vaccine in this population.

如右圖所示，我們的 mRNA-1608 疫苗在 HSV 病毒表面編碼抗原，並能夠誘導非常強的免疫反應。用 mRNA-1608 接種 HSV-2 疫苗後小鼠的中和滴度明顯高於血清陽性者的人類血清中的水平。這使我們有理由相信，我們將能夠為這一人群提供這種疫苗的顯著益處。

The second development candidate is on the following slide, Slide 25. This is our mRNA-1468 program against herpes zoster or shingles. Herpes zoster is caused by the reactivation of latent varicella-zoster virus or VZV for short. It's principally a disease that's seen as a result of declining immunity in older adults, where protection against VZV decline, leading to reactivation of the virus and painful and very itchy lesions. Herpes zoster occurs in about 1 out of 3 adults in their lifetime, and the incidence is increasing as populations age and particularly increases over the age of 50.

第二個開發候選者在下面的幻燈片中，幻燈片 25。這是我們針對帶狀皰疹或帶狀皰疹的 mRNA-1468 計劃。帶狀皰疹是由潛伏的水痘-帶狀皰疹病毒或簡稱VZV重新激活引起的。這主要是一種疾病，被認為是老年人免疫力下降的結果，對 VZV 的保護能力下降，導致病毒重新激活以及疼痛和非常癢的病變。帶狀皰疹發生在大約三分之一的成年人一生中，發病率隨著人口年齡的增長而增加，特別是在 50 歲以上。

On the right-hand side is previously published data in the Journal of Vaccine on our VZV vaccine; in this case, mRNA-1468. Our vaccine in nonhuman primates was compared against the protein and -- a protein plus adjuvant as a stand-in or proxy for the Shingrix vaccine, which is already approved for this indication. As you note on the right, in nonhuman primates, the mRNA vaccine against gE resulted in significant and elevated neutralizing titers after 2 doses and we believe will provide the basis for a strong potential clinical benefit with mRNA-1468.

右側是先前在《疫苗雜誌》上發表的關於我們 VZV 疫苗的數據；在這種情況下，mRNA-1468。我們在非人類靈長類動物中的疫苗與蛋白質和 - 一種蛋白質加佐劑作為 Shingrix 疫苗的替代品或替代品進行了比較，該疫苗已被批准用於該適應症。正如您在右側所指出的，在非人類靈長類動物中，針對 gE 的 mRNA 疫苗在 2 劑後導致顯著和升高的中和滴度，我們相信這將為 mRNA-1468 的強大潛在臨床益處提供基礎。

Moving now to our therapeutic pipeline. We continue to make progress across a range of different programs. On Slide 26, I'll note a few very quickly. First, our PCV program in Phase I is ongoing and the Phase II is fully enrolled. We expect data in the fourth quarter of 2022. We are also going to provide a bit of an update on the checkpoint vaccine and newly announced development candidate in just a minute.

現在轉到我們的治療管道。我們繼續在一系列不同的項目中取得進展。在幻燈片 26 上，我會很快注意到一些。首先，我們在第一階段的 PCV 計劃正在進行中，第二階段已完全註冊。我們預計 2022 年第四季度的數據。我們還將在一分鐘內提供有關檢查點疫苗和新宣布的開發候選者的一些更新。

Highlighting other therapeutic areas. Our VEGF program continues to move forward in Phase II with AstraZeneca. And in rare diseases, our PA and MMA programs continue to enroll in their Phase I, with the Phase I -- first dose-level cohort fully enrolled in PA and continued enrolling of additional cohorts. We also continue to make progress across all of our other preclinical programs in rare diseases, including GSD1a, PKU, CN-1 and the cystic fibrosis program with Vertex.

突出其他治療領域。我們的 VEGF 項目在阿斯利康的 II 期繼續推進。在罕見病方面，我們的 PA 和 MMA 項目繼續在其第一階段註冊，第一階段——第一個劑量水平的隊列完全註冊在 PA 中，並繼續招收更多的隊列。我們還繼續在我們所有其他罕見疾病的臨床前項目中取得進展，包括 GSD1a、PKU、CN-1 和 Vertex 的囊性纖維化項目。

On Slide 27, I'd like to briefly cover our latest development candidate, a checkpoint vaccine to promote anti-checkpoint T-cell responses in cancer, otherwise known as mRNA-4359. So briefly, the objective of this program is to stimulate effector T cells that target and kill suppressive immune and cancer cells that express high levels of targeted checkpoint antigen. It's been previously identified that there are pre-existing IDO and PD-L1 specific T cells that have been identified in cancer patients, in tumors. IDO and PD-L1 specific T cells can kill and remove the immunosuppressive regulatory Immune cells and cancer cells that overexpress these antigens. It's an important counterbalance that helps liberate the immune response against the tumor.

在幻燈片 27 上，我想簡要介紹一下我們最新開發的候選疫苗，一種用於促進癌症中抗檢查點 T 細胞反應的檢查點疫苗，也稱為 mRNA-4359。簡而言之，該計劃的目標是刺激靶向並殺死表達高水平靶向檢查點抗原的抑制性免疫細胞和癌細胞的效應 T 細胞。先前已經確定，在癌症患者和腫瘤中已經發現了預先存在的 IDO 和 PD-L1 特異性 T 細胞。 IDO 和 PD-L1 特異性 T 細胞可以殺死和清除過度表達這些抗原的免疫抑制調節性免疫細胞和癌細胞。這是一個重要的平衡，有助於釋放針對腫瘤的免疫反應。

Our vaccine can expand IDO and PD-L1 specific T cells in preclinical models. And the vaccine-induced direct tumor cell killing can facilitate recognition of tumor-associated antigens by other cytotoxic T cells, leading to more broad tumor kill. Systemic blockade with PD-1 or PD-L1 antibodies may further amplify this effect. We will initially be developing mRNA-4359 against indications including first-line cutaneous melanoma Stage IIIB and first-line non-small cell lung cancer.

我們的疫苗可以在臨床前模型中擴增 IDO 和 PD-L1 特異性 T 細胞。並且疫苗誘導的直接腫瘤細胞殺傷可以促進其他細胞毒性T細胞識別腫瘤相關抗原，從而導致更廣泛的腫瘤殺傷。用 PD-1 或 PD-L1 抗體進行全身性阻斷可能會進一步放大這種效應。我們最初將針對包括一線皮膚黑色素瘤 IIIB 期和一線非小細胞肺癌在內的適應症開發 mRNA-4359。

With that, I'd like to turn it over to David to walk you through the financials.

有了這個，我想把它交給大衛來引導你了解財務狀況。

Okay. Thank you, Stephen. We are providing today the analysis of actual 2021 fourth quarter and full year results along with a view of key drivers of financial performance going forward. 2021 was a transformative year for the company as it marked the transition from an R&D-focused entity to a commercial-stage company. I'm very pleased with our performance and wanted to thank all of our employees at Moderna for their dedication and response to the many challenges during this unprecedented company scale-up.

好的。謝謝你，斯蒂芬。我們今天提供對 2021 年第四季度和全年實際業績的分析，以及對未來財務業績的關鍵驅動因素的看法。 2021 年對公司來說是變革的一年，因為它標誌著從以研發為重點的實體向商業階段公司的轉變。我對我們的表現感到非常滿意，並要感謝 Moderna 的所有員工在這個前所未有的公司規模擴大過程中的奉獻精神和對許多挑戰的回應。

Turning now to Slide 29, starting with an overview of our sales performance. Total product sales in the fourth quarter of 2021 were $6.9 billion, representing 297 million doses delivered to our customers. This compares to sales of $4.8 billion for 208 million doses in Q3 and 199 million doses in Q2. We increased our dose supply in the fourth quarter by 43% compared to Q3 after a relatively stable picture in Q2 and Q3 as we successfully focused on removing bottlenecks in our supply chain network.

現在轉到幻燈片 29，從我們的銷售業績概述開始。 2021 年第四季度的產品總銷售額為 69 億美元，相當於向我們的客戶交付了 2.97 億劑。相比之下，第三季度 2.08 億劑和第二季度 1.99 億劑的銷售額為 48 億美元。在第二季度和第三季度相對穩定的情況下，我們在第四季度的劑量供應比第三季度增加了 43%，因為我們成功地專注於消除供應鍊網絡中的瓶頸。

Sales of our COVID vaccine have shifted in terms of geographic mix over the course of the year, in line with our expectations and the ramp-up of our international manufacturing capabilities. Sales outside the U.S. to the rest of the world were $6.1 billion in the fourth quarter, reflecting 252 million doses. And sales to the U.S. government were $0.7 billion in the fourth quarter, reflecting 45 million doses sold. For the full year, we sold 807 million doses, resulting in product sales of $17.7 billion. We generated sales of $5.4 billion in the U.S. and $12.3 billion with customers in the rest of the world. Approximately 25% of our delivered doses went to low- and middle-income countries, either through direct sales or facilitated by donations from other customers.

在這一年中，我們 COVID 疫苗的銷售在地域組合方面發生了變化，這符合我們的預期和我們國際製造能力的提升。第四季度美國以外對世界其他地區的銷售額為 61 億美元，反映了 2.52 億劑。第四季度對美國政府的銷售額為 7 億美元，售出 4500 萬劑。全年，我們銷售了 8.07 億劑，產品銷售額為 177 億美元。我們在美國的銷售額為 54 億美元，在世界其他地區的客戶銷售額為 123 億美元。我們交付的大約 25% 的劑量通過直接銷售或通過其他客戶的捐贈提供給了低收入和中等收入國家。

Turning to Slide 30 to go into more detail of our Q4 results. The transformation of Moderna from an R&D-focused biotech company to a commercial-stage business continues to be apparent when reviewing our financial results. The comparison of the fourth quarter of 2021 to prior year is not very meaningful due to the significant growth, which is why I'd primarily focus on the quarter-over-quarter comparison relative to Q3 on this slide.

轉向幻燈片 30，了解我們第四季度業績的更多細節。在審查我們的財務業績時，Moderna 從一家以研發為重點的生物技術公司向商業階段企業的轉變仍然顯而易見。由於顯著增長，2021 年第四季度與上一年的比較不是很有意義，這就是為什麼我在這張幻燈片上主要關注相對於第三季度的季度環比比較。

Total revenue was $7.2 billion in the fourth quarter of 2021 compared to $5 billion in the third quarter and $0.6 billion in the prior year period. The increase of total revenue was driven by the sale of the company's COVID-19 vaccine. Product sales in Q4 2021 were $6.9 billion compared to $4.8 billion in the third quarter, an increase of 44%.

2021 年第四季度的總收入為 72 億美元，而第三季度為 50 億美元，去年同期為 6 億美元。總收入的增長是由公司 COVID-19疫苗的銷售推動的。 2021 年第四季度的產品銷售額為 69 億美元，而第三季度為 48 億美元，增長了 44%。

Cost of sales was $952 million or 14% of company's product sales in the fourth quarter compared to $722 million or 15% of product sales in the third quarter. The quarter-over-quarter percentage improvement was driven by favorable manufacturing cost as the average selling price remained relatively stable.

第四季度銷售成本為 9.52 億美元，占公司產品銷售額的 14%，而第三季度為 7.22 億美元，佔產品銷售額的 15%。由於平均售價保持相對穩定，有利的製造成本推動了環比百分比的改善。

Research and development expenses were $648 million in the fourth quarter compared to $521 million in the third quarter and $759 million in the same period in 2020. The higher spend versus prior quarter was primarily driven by increased clinical trial expenses from our expanding and maturing development portfolio. The decrease in spending compared to 2020 was mainly due to the fact that the prior year number includes approximately $200 million of prelaunch inventory costs.

第四季度的研發費用為 6.48 億美元，而第三季度為 5.21 億美元，2020 年同期為 7.59 億美元。與上一季度相比，支出增加的主要原因是我們不斷擴大和成熟的開發組合增加了臨床試驗費用.與 2020 年相比，支出減少的主要原因是上一年的數字包括大約 2 億美元的發布前庫存成本。

Selling, general and administrative expenses were $201 million for Q4 compared to $168 million in the prior quarter and $79 million for the same period in the prior year. The growth in spending was driven by the commercialization of our COVID-19 vaccine globally, with continued investments in personnel and outside services in support of the accelerated company build-out.

第四季度的銷售、一般和管理費用為 2.01 億美元，上一季度為 1.68 億美元，去年同期為 7900 萬美元。我們的 COVID-19 疫苗在全球的商業化推動了支出的增長，並持續投資於人員和外部服務以支持公司加速擴張。

Provision for income taxes was $542 million in the fourth quarter, following $219 million in the third quarter and an insignificant amount in the prior year. Our effective tax rate for the fourth quarter was 10%. The quarter-over-quarter increase was primarily driven by higher earnings. Let me remind you of the fact that we had a net operating loss carryforward of $2.3 billion at the end of 2020. In 2021, we released the valuation allowance against the related deferred tax assets, which resulted in a nonrecurring full year benefit to our effective tax rate of about 5 percentage points.

第四季度所得稅撥備為 5.42 億美元，第三季度為 2.19 億美元，而上一年的數額微不足道。我們第四季度的有效稅率為 10%。環比增長主要是由較高的收益推動的。讓我提醒您一個事實，我們在 2020 年底結轉了 23 億美元的淨營業虧損。2021 年，我們針對相關遞延所得稅資產釋放了估值備抵，這為我們的有效稅率約為 5 個百分點。

We recorded net income of $4.9 billion in Q4 compared to $3.3 billion in Q3, an increase of 46%. This compares to a loss of $0.3 billion in Q4 of last year. Diluted earnings per share for Q4 2021 were $11.29.

我們在第四季度錄得 49 億美元的淨收入，而第三季度為 33 億美元，增長了 46%。相比之下，去年第四季度虧損 3 億美元。 2021 年第四季度的稀釋後每股收益為 11.29 美元。

Turning now to full year financial results on Slide 31. Total revenue was $18.5 billion for the full year 2021 compared to $0.8 billion in 2020. The significant growth was driven by the sales of 807 million doses of the company's COVID-19 vaccine, resulting in product sales of $17.7 billion. Cost of sales was $2.6 billion or 15% of the company's product sales in 2021, including third-party royalties of $641 million. A portion of the inventory costs associated with this year's product sales was expensed as prelaunch inventory in 2020. If inventories sold for the full year was valued at cost, our cost of sales for the period would have been $2.8 billion or 16% of product sales.

現在轉向幻燈片 31 上的全年財務業績。2021 年全年總收入為 185 億美元，而 2020 年為 8 億美元。公司的 COVID-19 疫苗銷售量為 8.07 億劑，推動了顯著增長，導致產品銷售額為 177 億美元。銷售成本為 26 億美元，占公司 2021 年產品銷售額的 15%，其中包括 6.41 億美元的第三方特許權使用費。與今年產品銷售相關的部分庫存成本在 2020 年作為發布前庫存計入費用。如果全年銷售的庫存按成本計價，我們在此期間的銷售成本將為 28 億美元或產品銷售額的 16% .

Research and development expenses were $2 billion in 2021 compared to $1.4 billion in 2020. The growth in spending in 2021 was driven by clinical trial expenses for our expanding pipeline and the related organizational build-out. Selling, general and administrative expenses were $0.6 billion for the full year 2021 compared to $0.2 billion in 2020. The growth in spending in 2021 was mainly due to increases in consulting and outside services, personnel-related costs, marketing expense and distributor fees primarily attributable to the company's COVID-19 vaccine commercialization-related activities and increased head count.

2021 年的研發費用為 20 億美元，而 2020 年為 14 億美元。2021 年支出的增長是由我們擴大管道和相關組織建設的臨床試驗費用推動的。 2021 年全年的銷售、一般和管理費用為 6 億美元，而 2020 年為 2 億美元。2021 年支出的增長主要是由於諮詢和外部服務、人事相關成本、營銷費用和分銷商費用增加所致公司的 COVID-19 疫苗商業化相關活動和增加的人數。

Provision for income taxes was $1.1 billion for the full year 2021 compared to an insignificant amount in 2020. The effective tax rate in 2021 was 8%. It was lower than the U.S. statutory rate primarily due to a nonrecurring benefit related to the release of the valuation allowance, the ongoing benefit of the foreign-derived intangible income deduction as well as benefits related to stock-based compensation.

2021 年全年的所得稅準備金為 11 億美元，而 2020 年的數額微不足道。2021 年的有效稅率為 8%。它低於美國的法定稅率，主要是由於與釋放估值津貼相關的非經常性收益、來自外國的無形收入扣除的持續收益以及與股票補償相關的收益。

Net income was $12.2 billion for the full year 2021 compared to a net loss of $0.8 billion in 2020. Diluted earnings per share were $28.29 for the full year 2021.

2021 年全年淨收入為 122 億美元，而 2020 年淨虧損為 8 億美元。2021 年全年每股攤薄收益為 28.29 美元。

Turning to cash and cash deposits on Slide 32. We ended 2021 with cash and investments of $17.6 billion compared to $15.3 billion at the end of Q3. The increase is driven by our commercial activity. The balance of cash deposits for future product supply was $6 billion at the end of the year compared to $6.7 billion at the end of Q3. The reduction quarter-over-quarter is driven by commercial deliveries against our commitments.

轉向幻燈片 32 上的現金和現金存款。截至 2021 年，我們的現金和投資為 176 億美元，而第三季度末為 153 億美元。增長是由我們的商業活動推動的。截至年底，未來產品供應的現金存款餘額為 60 億美元，而第三季度末為 67 億美元。季度環比減少是由於商業交付違背我們的承諾。

Now turning to Slide 33. Our capital allocation priorities remain unchanged. Our top investment priority has been and will continue to be reinvesting in the base business across multiple areas. For R&D, we have significantly increased our spending in 2021 to approximately $2 billion, and we expect to continue to further increase our spending in this area to advance and accelerate our pipeline, both for existing and new programs. We are also further increasing our investment into our global manufacturing network in digital, automation and AI as well as scaling up our global commercial operations.

現在轉到幻燈片 33。我們的資本配置重點保持不變。我們的首要投資重點一直是並將繼續在多個領域對基礎業務進行再投資。在研發方面，我們已將 2021 年的支出大幅增加至約 20 億美元，我們預計將繼續進一步增加在該領域的支出，以推進和加速我們現有和新項目的管道。我們還將進一步增加對我們在數字、自動化和人工智能方面的全球製造網絡的投資，並擴大我們的全球商業運營。

Our second investment priority is to seek attractive external investment and collaboration opportunities to further expand the reach of Moderna's technology and capabilities. We are considering attractive opportunities that enable and complement our platform and take a disciplined approach in evaluating potential outside investments. Our announced collaborations with Metagenomi and Carisma Therapeutics fall into this category.

我們的第二個投資重點是尋求有吸引力的外部投資和合作機會，以進一步擴大 Moderna 的技術和能力範圍。我們正在考慮具有吸引力的機會，以支持和補充我們的平台，並採取嚴格的方法評估潛在的外部投資。我們宣布與 Metagenomi 和 Carisma Therapeutics 的合作屬於這一類。

After evaluating internal and external investment opportunities, we then assess additional uses of cash. We announced a $1 billion share buyback program in August of last year, which we completed in January of this year. As part of today's press release, we announced that the Board has authorized a new share buyback program of $3 billion.

在評估內部和外部投資機會後，我們會評估現金的其他用途。我們在去年 8 月宣布了一項價值 10 億美元的股票回購計劃，並於今年 1 月完成。作為今天新聞稿的一部分，我們宣布董事會已批准一項 30 億美元的新股票回購計劃。

Similar to last year, we provide you with a financial framework for 2022, which you will find on Page 34. We have signed advanced purchase agreements for expected delivery in 2022 in the amount of approximately $19 billion and signed option agreements for delivery in 2022 of approximately $3 billion on a probabilitized basis. In 2022, we believe that the SARS-CoV-2 virus will evolve to an endemic phase. And as a result, we expect the timing of sales to be larger in the second half of 2022 than the first half.

與去年類似，我們為您提供了 2022 年的財務框架，您可以在第 34 頁找到該框架。我們已簽署預購協議，預計 2022 年交付，金額約為 190 億美元，並簽署了 2022 年交付的期權協議按概率計算，約 30 億美元。 2022 年，我們認為 SARS-CoV-2 病毒將發展到流行階段。因此，我們預計 2022 年下半年的銷售時間將大於上半年。

Our total cost of sales includes the cost of goods manufactured, third-party royalties as well as logistics and warehousing costs. For the full year 2022, we expect a cost of sales ratio in the low to mid-20s percent range. The increase compared to prior year is driven by an expected increase in manufacturing costs as well as a decrease in expected average selling price per dose. The forecast increase of manufacturing costs is primarily driven by higher costs for fill-finish activities due to an expected shift from pandemic pack sizes to smaller dose and vial presentations. The decrease in average selling price is driven by the forecast increased deliveries to low-income countries.

我們的總銷售成本包括商品製造成本、第三方特許權使用費以及物流和倉儲成本。對於 2022 年全年，我們預計銷售成本比率將在 20% 到 20% 的範圍內。與上一年相比的增長是由預期的製造成本增加以及每劑預期平均售價的下降推動的。製造成本的預測增長主要是由於填充完成活動的成本增加，這是由於預期從大流行包裝尺寸轉向更小的劑量和小瓶展示。平均售價下降的原因是預計向低收入國家的交付量增加。

For R&D and SG&A expenses, we expect full year expenses to be approximately $4 billion, driven by our maturing development portfolio and the global scale-up of the company. Based on current tax laws, we expect our 2022 tax rate to be in the mid-teens as a result of the benefits from foreign-derived intangible income, driven by our international business mix and stock-based compensation deductions. Finally, regarding capital expenditures, we are planning for capital expenditures in the range of $0.6 billion to $0.8 billion as we further build out our manufacturing and general company infrastructure globally.

對於研發和 SG&A 費用，我們預計全年費用約為 40 億美元，這主要得益於我們成熟的開發組合和公司在全球的擴張。根據現行稅法，我們預計 2022 年的稅率將在十幾歲左右，這是由於我們的國際業務組合和基於股票的薪酬扣除推動了來自外國的無形收入的好處。最後，關於資本支出，隨著我們進一步在全球範圍內建設製造和一般公司基礎設施，我們計劃資本支出在 6 億美元至 8 億美元之間。

This concludes my remarks concerning the financial performance. And I now turn the call over to Stephane.

我對財務業績的評論到此結束。我現在把電話轉給斯蒂芬。

Thank you, David, Stephen and Paul. Let me now share some thoughts about where we're heading. I am pleased to see how the team is executing on our product strategy.

謝謝大衛、斯蒂芬和保羅。現在讓我分享一些關於我們前進方向的想法。我很高興看到團隊如何執行我們的產品戰略。

Priority #1, pan-respiratory annual booster. RSV is already in Phase III. We are waiting for flu data to start the Phase III on flu and start the Phase I on COVID plus flu candidate, mRNA-1073. Priority #2, latent viruses vaccines. With CMV in Phase III, now we have 5 candidates, including VZV against shingles, and more coming. Priority #3 therapeutics. We have a new checkpoint cancer vaccine. And priority #4, expanding our unique mRNA platform to create new medicine.

優先級 #1，泛呼吸年度助推器。 RSV 已經處於第三階段。我們正在等待流感數據開始流感的第三階段，並開始 COVID 和流感候選藥物 mRNA-1073 的第一階段。優先事項 #2，潛伏病毒疫苗。隨著 CMV 在第三階段，現在我們有 5 個候選者，包括 VZV 對抗帶狀皰疹，還有更多候選者。優先 #3 治療。我們有一種新的檢查點癌症疫苗。優先事項 #4，擴展我們獨特的 mRNA 平台以創造新藥。

As I shared in January at the JPMorgan Healthcare Conference, there was a big change in commercial momentum for Moderna between early 2021 and early 2022. In early 2021, both mRNA vaccines looked the same after Phase III data, and now we see strong real-world evidence that Spikevax has long duration of efficacy. In early 2021, we were supply constrained, and now we're getting to a place we continue to scale manufacturing, thanks to investments made last year and are less supply constrained. We have contracts with many governments around the world, but in early 2021, we have a few team members on the ground in most countries.

正如我在 1 月份在摩根大通醫療保健會議上分享的那樣，Moderna 的商業動力在 2021 年初至 2022 年初之間發生了巨大變化。在 2021 年初，兩種 mRNA 疫苗在 III 期數據後看起來都一樣，現在我們看到了強勁的真實-世界證據表明，Spikevax 的療效持續時間長。在 2021 年初，我們受到供應限制，現在由於去年的投資和供應限制較少，我們正在繼續擴大製造規模。我們與世界各地的許多政府都有合同，但在 2021 年初，我們在大多數國家/地區都有一些團隊成員。

On Slide 37, you can see that Spikevax booster market share has increased across key markets. You see that shift in market share data from around the world where we have teams on the ground. Even in Germany, where there is national mRNA champion, we have moved our share of the booster market from 4% in October 2021 to almost 40% in January 2022. And it is also clear that OECD countries or high-income countries have become de facto mRNA market.

在幻燈片 37 上，您可以看到 Spikevax 助推器在主要市場的市場份額有所增加。您會看到我們在當地設有團隊的世界各地的市場份額數據發生了變化。即使在擁有全國 mRNA 冠軍的德國，我們的助推器市場份額也從 2021 年 10 月的 4% 提高到 2022 年 1 月的近 40%。而且很明顯，經合組織國家或高收入國家已成為事實上的 mRNA 市場。

We have continued to increase our signed APAs to now around $19 billion. We also have approximately $3 billion in probabilized options. We continue to have numerous discussions with government and NGOs around the world. For example, the current U.S. contract has its last shipments coming before the summer of 2022. This means that in the $19 billion plus $3 billion option, there is currently no APAs for the U.S. for the second half of 2022. As David mentioned, when we shift into endemic, we expect seasonality in sales. This year, we expect to see continued primary vaccination and boosting in the Southern Hemisphere in the first half and a shift to boosters as a fourth dose booster in the Northern Hemisphere in the second half of the year, similar to flu vaccines.

我們繼續將簽署的 APA 增加到現在的 190 億美元左右。我們還有大約 30 億美元的概率期權。我們繼續與世界各地的政府和非政府組織進行多次討論。例如，目前的美國合同的最後一批貨物是在 2022 年夏季之前。這意味著在 190 億美元加 30 億美元的期權中，目前美國沒有 2022 年下半年的 APA。正如大衛所說，當我們轉變為地方病，我們預計銷售會出現季節性變化。今年，我們預計南半球將在上半年繼續進行初級疫苗接種和加強免疫，並在今年下半年在北半球轉向加強劑作為第四劑加強劑，類似於流感疫苗。

We were pleased to announce last week a big expansion of our commercial network. From our current 11 countries where we have Moderna commercial teams on the ground, we announced an additional 10 countries: in Europe, Poland, Netherlands, Belgium, Sweden, Norway and Denmark; and in Asia, Malaysia, Taiwan, Singapore, Hong Kong.

上週，我們很高興地宣布我們的商業網絡的大規模擴展。在我們目前有 Moderna 商業團隊的 11 個國家中，我們宣布了另外 10 個國家：歐洲、波蘭、荷蘭、比利時、瑞典、挪威和丹麥；在亞洲，馬來西亞，台灣，新加坡，香港。

You have seen the impact of our strong real-world evidence data, coupled with teams on the ground, drive greater Moderna market penetration. I believe the same phenomena will happen in those 10 new markets.

您已經看到我們強大的真實世界證據數據的影響，加上實地團隊，推動了 Moderna 更大的市場滲透。我相信這10個新市場也會出現同樣的現象。

With a direct commercial presence in these 21 important markets, we'll maximize the impact of Spikevax and also have the teams to launch our pan-respiratory annual booster or latent virus vaccines and the rest of the portfolio. That commercial coverage and capabilities will prove critical in our ability to maximize our impact on patients and the resulting value creation. We now have distributors in Central and Eastern Europe. We have distributors in Asia Pacific and with this week announcement, in Latin America. We, of course, continue to work with COVAX to provide access to our vaccines to low-income countries.

憑藉在這 21 個重要市場的直接商業存在，我們將最大限度地發揮 Spikevax 的影響，並讓團隊推出我們的泛呼吸道年度加強或潛伏病毒疫苗以及其他產品組合。這種商業覆蓋和能力將證明我們能夠最大限度地發揮對患者的影響以及由此產生的價值創造的關鍵。我們現在在中歐和東歐都有經銷商。我們在亞太地區有經銷商，本周宣佈在拉丁美洲有經銷商。當然，我們將繼續與 COVAX 合作，為低收入國家提供我們的疫苗。

Strategically, we want to create a new business model with governments around -- for pan-respiratory annual booster. We have started to create a subscription or service model with governments around the world. We have announced memoranda of understanding with the governments of Canada and Australia. We are currently in discussions with several other countries. These are 10-year agreements for the supply of pan-respiratory annual booster. We have also governments which have signed APAs for 2023, as you can see on the slide. Numerous discussions are ongoing as we speak about securing supply for 2023 for the endemic setting to protect people at risk: 15 years old and above, people with comorbidity factors, people whose job put them at risk and adults who simply do not want to get severe disease.

從戰略上講，我們希望與政府一起創建一種新的商業模式——用於泛呼吸年度助推器。我們已經開始與世界各地的政府建立訂閱或服務模式。我們已經宣布了與加拿大和澳大利亞政府的諒解備忘錄。我們目前正在與其他幾個國家進行討論。這些是泛呼吸年度助推器供應的 10 年期協議。正如您在幻燈片上看到的那樣，我們也有政府簽署了 2023 年的預約定價安排。當我們談論確保 2023 年流行環境的供應以保護處於危險中的人時，正在進行許多討論：15 歲及以上、有合併症因素的人、工作使他們處於危險之中的人以及根本不想變得嚴重的成年人疾病。

As we shared in the past, this is our strategy for capital allocation. As David said, the priority #1 is and remains to invest in the company. We have this unique mRNA platform, and we have $17 billion to invest to grow our pipeline to launch new medicine and to expand the capabilities of our platform. Priority #2 is to expand the platform by in-licensing or M&A as we see new interesting nucleic acid technologies that can complement and strengthen the Moderna platform. Priority #3 is to return capital to shareholders. After completing our August 2021 $1 billion share buyback plan and reducing our share count for the first time, we announced this morning a new $3 billion share buyback.

正如我們過去所分享的，這是我們的資本配置策略。正如大衛所說，第一要務是並且仍然是投資公司。我們擁有這個獨特的 mRNA 平台，我們有 170 億美元的投資來發展我們的管道，以推出新藥並擴大我們平台的能力。優先事項 #2 是通過許可或併購來擴展平台，因為我們看到新的有趣的核酸技術可以補充和加強 Moderna 平台。優先事項 #3 是向股東返還資本。在完成 2021 年 8 月的 10 億美元股票回購計劃並首次減少股票數量後，我們今天上午宣布了新的 30 億美元股票回購計劃。

As we grow Moderna, we care deeply about building the right company which is a responsible company to its community. In 2021, 25% of doses we shipped were to low- and middle-income countries. We're investing in Moderna Science Center in Cambridge and launching an AI academy.

隨著 Moderna 的發展，我們非常關心建立合適的公司，成為對其社區負責的公司。 2021 年，我們運送的 25% 的劑量是發往低收入和中等收入國家的。我們正在投資劍橋的 Moderna 科學中心，並開設一所人工智能學院。

We plan to achieve net 0 carbon emissions globally by 2030. We've announced Moderna Charitable Foundation and the global fellowship program. And we announced plans to invest up to $500 million in manufacturing facility in Africa. We hope to be able to announce some positive developments soon about these exciting projects. We will continue to [put importance on] corporate social responsibilities and share this with you.

我們計劃到 2030 年在全球實現零碳排放。我們宣布了 Moderna Charitable Foundation 和全球獎學金計劃。我們宣布計劃在非洲投資高達 5 億美元的製造設施。我們希望能夠很快宣布這些令人興奮的項目的一些積極進展。我們將繼續[重視]企業社會責任，並與您分享。

Before taking your questions, we'd like to remind you of 2022 events. March 24 will be our Annual Vaccine Day. May 17 will be our Annual Science Day, where we'll present new platform advances. September 8 will be our Annual R&D Day, where we present development pipeline key updates. And today, we're announcing that we'll be hosting our first ESG Day on November 10.

在回答您的問題之前，我們想提醒您 2022 年的事件。 3 月 24 日將是我們一年一度的疫苗日。 5 月 17 日將是我們的年度科學日，屆時我們將展示新的平台進展。 9 月 8 日將是我們的年度研發日，我們將在此展示開發管道的關鍵更新。今天，我們宣布將於 11 月 10 日舉辦我們的第一個 ESG 日。

I would like to close by sharing how excited we are about the future of our company. Because mRNA is an information molecule, we always knew this will be a company with 0 drug approach or not. Well, now we know which future it will be.

最後，我想分享一下我們對公司的未來感到多麼興奮。因為 mRNA 是一種信息分子，所以我們一直都知道這將是一家採用 0 藥物途徑的公司。好吧，現在我們知道它將是哪個未來。

We are passionate about our ability to have a profound impact on humanity. We believe nobody should be hospitalized because of a respiratory virus. We have the technology to do that. We believe nobody should have medical consequences short term or long term because of a latent virus. We have a technology to do that. We believe we can have a profound impact on disease treatments with our therapeutics first and then our gene-editing programs. This is just the beginning.

我們對我們對人類產生深遠影響的能力充滿熱情。我們認為沒有人應該因為呼吸道病毒而住院。我們有技術可以做到這一點。我們相信沒有人應該因為潛伏病毒而產生短期或長期的醫療後果。我們有技術可以做到這一點。我們相信，首先通過我們的治療方法，然後是我們的基因編輯程序，我們可以對疾病治療產生深遠的影響。這僅僅是個開始。

Operator, we'll be happy to take your questions.

接線員，我們很樂意回答您的問題。

(Operator Instructions) Our first question comes from Salveen Richter with Goldman Sachs.

（操作員說明）我們的第一個問題來自高盛的 Salveen Richter。

Outside of the flu data that we're going to see this year, we're going to get personalized cancer vaccine data as well as rare disease data. Could you just speak to, in rare disease, what success would look like and what the regulatory path there could be; and then for the personalized cancer vaccine, whether we would be able to get a sense of proof of concept this year?

除了今年我們將看到的流感數據之外，我們還將獲得個性化的癌症疫苗數據以及罕見病數據。您能否談談在罕見病領域取得怎樣的成功以及可能的監管路徑？那麼對於個性化的癌症疫苗，今年我們是否能夠獲得概念驗證的感覺呢？

Sure. Thank you for the question, Salveen. So first, in the rare disease space, it's important to recognize that these are Phase I/II studies, both the PA and MMA study. And I'll speak to the PA study mostly because, as I said a moment ago, it's the one that is -- has enrolled its first cohort and is moving forward with enrollment.

當然。謝謝你的問題，薩爾文。因此，首先，在罕見病領域，重要的是要認識到這些是 I/II 期研究，包括 PA 和 MMA 研究。我將談到 PA 研究，主要是因為，正如我剛才所說，它是 - 已經註冊了第一批隊列並且正在推進註冊。

So first and foremost, we are going to be looking at safety in these studies, as you'd expect from a Phase I/II. And so one of the most important things to establish is can we continue to dose, unfortunately, very ill people and ill children in the case of both of these studies with mRNA LNPs for up to 6 months or even longer if they stay on the open-label extension. And establishing the safety of the platform on chronic dosing repeatedly over 6 to 12 months is an important objective of that part of the study.

因此，首先，我們將在這些研究中關注安全性，正如您對 I/II 階段的期望一樣。因此，要確定的最重要的事情之一是，不幸的是，在這兩項研究的情況下，我們能否繼續給重病患者和生病的兒童服用 mRNA LNP 長達 6 個月甚至更長時間，如果他們保持開放狀態的話-標籤擴展。並且在 6 到 12 個月內反復建立長期給藥平台的安全性是該部分研究的一個重要目標。

When it comes to efficacy, again, these are early studies and small in number as usually is the case with rare diseases. And so I have to be careful about interpreting any of the data from the early clinical reads too concretely. But the things we'll be looking for, first and foremost, we'll be looking at the performance of the medicines in terms of preventing clinical outcomes. And so in the case of propionic acidemia, these will be major metabolic decompensation events or hospitalizations that do happen with some regularity, unfortunately, for those folks who suffer from these rare diseases or diseases like PA.

同樣，在療效方面，這些都是早期研究，而且數量很少，就像罕見病的情況一樣。因此，我必須小心謹慎地解釋早期臨床讀數中的任何數據。但我們首先要尋找的東西，我們將著眼於藥物在預防臨床結果方面的表現。因此，在丙酸血症的情況下，不幸的是，對於那些患有這些罕見疾病或 PA 等疾病的人來說，這些將是有規律地發生的重大代謝失代償事件或住院治療。

And we will also be looking at biomarkers and so specifically, biomarkers that have correlated with preclinical disease and perhaps to a lesser extent, with some of the existing transplant-based therapeutic interventions in these diseases. But it's important to note that across all of these things in the biomarker space, there are not, unfortunately, validated biomarkers for these diseases because there have not yet been therapeutics approved. And so it will be a balance between looking at efficacy signals early, to be fair, potential signals of improvements in clinical outcomes and looking at biomarkers across a relatively small number of individuals. And so there will be heterogeneous disease, both genetically and in terms of their performance.

我們還將研究生物標誌物，特別是與臨床前疾病相關的生物標誌物，也許在較小程度上與這些疾病中一些現有的基於移植的治療干預相關。但重要的是要注意，在生物標誌物領域的所有這些事情中，不幸的是，這些疾病沒有經過驗證的生物標誌物，因為尚未批准治療方法。因此，在早期觀察療效信號（公平地說，臨床結果改善的潛在信號）和觀察相對少數個體的生物標誌物之間將取得平衡。因此，無論是在遺傳上還是在表現方面，都會出現異質性疾病。

Our hope is when we get composite of data that's clear, that we'll be able to then present that and have discussions with regulators, which is the second part of your question, and have a discussion about what outcomes matter most for a potential pivotal study if we continue forward. But we do believe that the things that will ultimately matter most are clinical outcomes and so the prevention of major decompensation events and hospitalizations and obviously, although the studies will be small in patient number, perhaps even hospitalization and death. So we'll be looking for those sorts of signals from our early studies.

我們的希望是，當我們獲得清晰的數據組合時，我們將能夠展示它並與監管機構進行討論，這是您問題的第二部分，並討論哪些結果對潛在的關鍵問題最重要如果我們繼續前進，請學習。但我們確實認為，最終最重要的是臨床結果，以及預防重大失代償事件和住院治療，顯然，儘管這些研究的患者人數很少，甚至可能住院和死亡。因此，我們將從早期研究中尋找這些信號。

But it's important to recognize, as I said a moment ago, these are relatively small in number and we'll want to be circumspect in how we move forward into those efficacy studies. And those regulatory consultations will be based on those data, and we'll provide updates when we have it.

但重要的是要認識到，正如我剛才所說，這些數量相對較少，我們希望在如何推進這些功效研究時保持謹慎。這些監管諮詢將基於這些數據，我們將在獲得這些數據時提供更新。

On the PCV program, as you said, we have completed enrollment in the Phase II study of PCV. And we expect that, that PCV -- as a reminder, that is a head-to-head comparison of KEYTRUDA alone versus KEYTRUDA plus vaccine. And we're looking at relapse-free survival in approximately 1 year. That data we would expect to come in the fourth quarter of this year.

關於 PCV 項目，正如您所說，我們已經完成了 PCV II 期研究的註冊。我們希望 PCV 提醒一下，這是單獨 KEYTRUDA 與 KEYTRUDA 加疫苗的頭對頭比較。我們正在研究大約 1 年的無復發生存期。我們預計該數據將在今年第四季度發布。

And because it is a randomized head-to-head study, I could provide a clear signal of the potential benefit of personalized cancer vaccines versus KEYTRUDA alone, which is obviously the standard we're going for. That data would emerge based on when we complete enrollment and announce that completement in the fourth quarter of this year. And based on that data, we would consult with regulators and obviously decide how to proceed forward if it's positive.

而且因為這是一項隨機的頭對頭研究，我可以提供一個明確的信號，表明個性化癌症疫苗與單獨使用 KEYTRUDA 相比具有潛在益處，這顯然是我們要追求的標準。該數據將基於我們何時完成註冊並在今年第四季度宣布完成。根據這些數據，我們將與監管機構協商，如果結果是肯定的，顯然會決定如何進行。

Our next question comes from Gena Wang with Barclays.

我們的下一個問題來自巴克萊銀行的 Gena Wang。

I have 2 questions. So the first one is regarding the flu data, the Phase II data in early 2022. Can you be a little bit more specific on timing? And what kind of data you think that could be fileable without the need of a Phase III trial with the efficacy outcome?

我有 2 個問題。所以第一個是關於流感數據，即 2022 年初的 II 期數據。你能在時間上更具體一點嗎？您認為哪些數據可以在不需要具有療效結果的 III 期試驗的情況下歸檔？

The second question is regarding the 1273 U.S. aged 12 to 17. In the press release, you said FDA has not concluded on benefit/risk profile of 100-microgram primary series. What additional data you would need to provide? And will you need to provide 50-microgram data in order to receive approval?

第二個問題是關於 1273 名 12 至 17 歲的美國人。在新聞稿中，您說 FDA 尚未就 100 微克初級系列的益處/風險概況作出結論。您需要提供哪些額外數據？您是否需要提供 50 微克的數據才能獲得批准？

Great. Thank you, Gena, for both those questions. So first, a clarification on the flu data. We do not believe that the Phase II data alone would be fileable. And that's based on previously published regulatory guidance, not specific guidance to Moderna, that ultimately, we don't think Phase II on flu alone, which is an immunogenicity -- safety and immunogenicity study of approximately several hundred, is sufficient for filing.

偉大的。謝謝你，Gena，這兩個問題。首先，澄清流感數據。我們不認為僅 II 期數據是可歸檔的。這是基於先前發布的監管指南，而不是針對 Moderna 的具體指南，最終，我們認為僅針對流感的 II 期，這是一項免疫原性——大約數百項的安全性和免疫原性研究，不足以提交申請。

The question is, from a filing perspective, what sorts of Phase III studies are necessary and whether or not an accelerated approval is possible based on just safety and immunogenicity or whether we will need to demonstrate efficacy in an independent efficacy study, a Phase III efficacy study prior to filing. And those are consultations that have not yet happened with regulators but will on the back of that Phase II data that we expect shortly. It's important to note that there are precedents for accelerated approvals based just on safety and immunogenicity in a Phase III study, which would be a few thousand people. But you always have to then follow up with an efficacy study perhaps post approval.

問題是，從備案的角度來看，什麼樣的 III 期研究是必要的，是否可以僅基於安全性和免疫原性加速批准，或者我們是否需要在獨立的療效研究中證明療效，即 III 期療效申請前學習。這些是尚未與監管機構進行的磋商，但將在我們預計不久的第二階段數據的支持下進行。重要的是要注意，在 III 期研究中，僅基於安全性和免疫原性就有加速批准的先例，這將是幾千人。但是你總是必須跟進一項功效研究，也許是在批准後。

And so in summary, we expect to have to do an efficacy study in flu at some point. The question is whether or not it would be before or after accelerated approval with a Phase III immunogenicity and safety study. That Phase III study would follow on the current Phase II study, and we don't think that the Phase II study alone is fileable. We do intend, as I said previously and we've said before, to try and start those Phase III studies, whether they're efficacy, safety, immunogenicity study, this year.

總而言之，我們預計在某個時候必須對流感進行療效研究。問題是它是在加速批准 III 期免疫原性和安全性研究之前還是之後。該 III 期研究將在當前 II 期研究之後進行，我們認為僅 II 期研究是不可歸檔的。正如我之前所說和我們之前所說，我們確實打算在今年嘗試啟動這些 III 期研究，無論它們是有效性、安全性還是免疫原性研究。

On the question of the 1273 adolescent filing within the U.S., and so the FDA has not provided -- has not completed its review of the 100-microgram adolescent primary series. And we have decided on consultation with them to evaluate a lower dose, a 50-microgram primary series dose in -- of adolescents 12 to 17. It's important to note that the 12 to 17 adolescent 100-microgram primary series has been approved globally in many other markets and we believe has been administered quite broadly, perhaps up to over 1 million adolescents globally. And so we'll continue to collect that real-world data as well as the observational data from our monitoring studies and as and when appropriate, submit that to the FDA for their continued evaluation of the 100-microgram primary series.

關於美國境內 1273 青少年申請的問題，因此 FDA 沒有提供 - 尚未完成對 100 微克青少年初級系列的審查。我們已決定與他們協商，以評估 12 至 17 歲青少年的較低劑量，即 50 微克初級系列劑量。重要的是要注意，12 至 17 歲青少年 100 微克初級系列已在全球獲得批准許多其他市場，我們相信已經得到了相當廣泛的管理，全球可能多達 100 萬青少年。因此，我們將繼續從我們的監測研究中收集真實數據以及觀察數據，並在適當的時候將其提交給 FDA 以繼續評估 100 微克初級系列。

We are in the interim -- given the strong real-world efficacy data that we've seen for Spikevax or mRNA-1273 particularly in immune-compromised population, we are in the interim preparing an EUA filing in the United States for 100 micrograms for immune-compromised adolescents or those at high risk of severe outcomes from disease because we think the strong efficacy profile of mRNA-1273 at 100 micrograms provides a clear benefit/risk in that population. We do believe that 100 micrograms provides a benefit more broadly, which is why it's been authorized globally, but we'll continue to work with the FDA and the U.S. to evaluate other potential dose-sparing strategies and submit that data as we develop it.

我們處於過渡階段——鑑於我們已經看到 Spikevax 或 mRNA-1273 的強大的真實世界療效數據，特別是在免疫受損人群中，我們正在準備在美國提交一份 100 微克的 EUA 申請因為我們認為 100 微克 mRNA-1273 的強大功效特徵在該人群中提供了明顯的益處/風險。我們確實相信 100 微克可提供更廣泛的益處，這就是它在全球獲得授權的原因，但我們將繼續與 FDA 和美國合作，評估其他潛在的劑量節約策略，並在我們開發時提交該數據。

Our next question comes from Matthew Harrison with Morgan Stanley.

我們的下一個問題來自摩根士丹利的 Matthew Harrison。

I have 2 clarifications and then a question. So first one, on flu. Should we expect that when you present to us the Phase II data, whether or not you'll have had those regulatory discussions, we'd be able to talk about potential next steps in terms of what scope of Phase III studies you would need? And then second, on PA, can you give us a sense of how many cohorts you think you need to see before you may be able to provide that initial data?

我有兩個澄清，然後是一個問題。所以第一個，關於流感。我們是否應該期望，當您向我們展示 II 期數據時，無論您是否進行過這些監管討論，我們都能夠就您需要的 III 期研究範圍討論潛在的後續步驟？其次，在 PA 上，您能否告訴我們您認為需要查看多少個群組才能提供初始數據？

And then third, just on the timing of COVID revenues this year. I believe at JPM, you had talked more about first half weighting than second half weighting, and it seems like that's switched. And I've gotten just a couple of questions that I thought would be helpful to clarify. Is that mainly because you're now targeting boosters for the fall? Or is there something else happening here in terms of the weighting of the revenues?

第三，就在今年 COVID 收入的時間安排上。我相信在摩根大通，你更多地談論上半年的權重而不是下半年的權重，而且似乎已經改變了。我只收到了幾個我認為有助於澄清的問題。這主要是因為你現在的目標是秋季的助推器嗎？還是在收入權重方面發生了其他事情？

So thanks, Matthew. I'll take the first 2 questions. So first, on flu, it's obviously not in our hands alone, we will -- whether we would be able to connect with the FDA and get feedback back. As we all know, the agency globally but also the agency in the United States, agencies are -- have a lot going on right now. And so there may be some delays in getting that feedback.

所以謝謝，馬修。我會回答前兩個問題。因此，首先，在流感方面，這顯然不是我們一個人的事情，我們將——我們是否能夠與 FDA 聯繫並獲得反饋。眾所周知，全球的代理機構以及美國的代理機構，現在都有很多事情要做。因此，獲得該反饋可能會有一些延遲。

So it is not -- we will probably share the Phase II data as we have it. And we will obviously rapidly consult with agencies, but we will not gate on hearing back from agencies before we share that data. And our plans are moving forward. But if it's possible to get that response more quickly, obviously, that will be something we'll share at that time. So I wouldn't expect it is the short version, being able to have that agency feedback. But it's possible, and we'll keep our fingers crossed that perhaps the agencies can turn that around more quickly.

所以它不是——我們可能會分享我們擁有的第二階段數據。我們顯然會迅速與機構協商，但在我們分享這些數據之前，我們不會在收到來自機構的回音時採取行動。我們的計劃正在向前推進。但是，如果有可能更快地得到響應，很明顯，這將是我們屆時將分享的內容。所以我不希望它是簡短版本，能夠獲得該機構的反饋。但這是可能的，我們會祈禱，也許這些機構可以更快地扭轉局面。

On PA, so the number of dose-level cohorts. I think it's important to say that there are sort of 2 features here that we'll be looking at: obviously, the dose-level cohorts, so how many different dose-level or dose-frequency cohorts that we're looking at in that study; but also then, the duration of time on that study because the primary objective of the intervention -- of the PA program particularly is to prevent the major metabolic decompensations. And so that is also something that requires time to accrue so that you can understand, within an individual patient, whether you've changed the rate of those recurring events.

在 PA 上，劑量水平隊列的數量也是如此。我認為重要的是要說這裡有兩個特徵我們將要研究：顯然，劑量水平群組，我們正在研究多少不同的劑量水平或劑量頻率群組學習;而且，該研究的持續時間，因為乾預的主要目標 - 特別是 PA 計劃的主要目標是防止主要的代謝失代償。因此，這也需要時間來積累，以便您可以了解，在個別患者中，您是否改變了這些重複事件的發生率。

And so it's a mix of 2 things. I mean, I think we would probably expect to see 2 to 3 dose-level cohorts. But also, given the rate of enrollment, that would probably also allow us to accrue approximately 1 year on drug for many of the early recipients. And that combination, those who've been on for a while as well as seeing what dose escalation can achieve perhaps in biomarkers, will be the composite data that we think will allow us to make a determination whether we've got the right dose level and whether we've got a clear indication of benefit and obviously, whether or not we're seeing chronic safety and tolerability, which we will expect. And if we have that data and it feels clear, then we will move to regulatory consultation on the next step of clinical studies and obviously, update all of you with that information. So not a concrete number of dose-level cohorts but more a function of both time on drug for the early cohorts and perhaps a second or third dose-level cohort of data that will provide us with that clarity.

所以這是兩件事的混合。我的意思是，我認為我們可能希望看到 2 到 3 個劑量水平的隊列。而且，考慮到入學率，這也可能讓我們為許多早期接受者積累大約 1 年的藥物治療時間。這種組合，那些已經使用了一段時間的人，以及看到可能在生物標誌物中達到什麼劑量升級，將是我們認為將使我們能夠確定我們是否得到正確劑量水平的複合數據以及我們是否有明確的益處跡象，顯然，我們是否看到了長期安全性和耐受性，這是我們所期望的。如果我們有這些數據並且感覺很清楚，那麼我們將就下一步的臨床研究進行監管諮詢，顯然，用這些信息更新你們所有人。因此，不是具體數量的劑量水平隊列，而更多的是早期隊列的藥物治療時間以及可能為我們提供清晰性的第二或第三劑量水平數據隊列的函數。

And I'll turn it over to, I think, David for the third question.

對於第三個問題，我想我會把它交給大衛。

Yes. So in terms of the first half, second half timing, as we've looked now at -- as we move into '22, what do we see? We see that the emerging market countries of COVAX have indicated that they're having a lot of challenge to absorb all the product that they're receiving through donations. And therefore, as we looked at in particular the second quarter timing versus the third quarter, we refined that outlook to be, as I described, first half, second half. And then secondly, the second half is certainly -- as Stephane mentioned, we think there's going to be quite strong booster sales that will cause the second half to be a bit higher than the first half.

是的。因此，就上半場、下半場時間而言，正如我們現在所看到的那樣——當我們進入 22 世紀時，我們看到了什麼？我們看到，COVAX 的新興市場國家表示，他們在吸收通過捐贈獲得的所有產品方面面臨著很大的挑戰。因此，當我們特別關注第二季度與第三季度的時間安排時，我們將這一前景細化為，正如我所描述的那樣，上半年和下半年。其次，下半年肯定是 - 正如斯蒂芬所說，我們認為將會有相當強勁的助推器銷售，這將導致下半年略高於上半年。

Your next question comes from Michael Yee with Jefferies.

您的下一個問題來自 Jefferies 的 Michael Yee。

We had a 2-part question. One was thinking about your COVID booster strategy and the 3 different strategies you laid out, including the bivalent, which I think is great. Can you just talk about at what point you would decide to pick which strategy that would be and you're confident that whatever that would be, that, that would be ready and able to be approved by the FDA to distribute presumably for the fall 2022 booster season and if that is actually the product that would be in the guidance for 2022?

我們有一個兩部分的問題。一個是考慮您的 COVID 助推器策略以及您制定的 3 種不同策略，包括二價策略，我認為這很棒。您能否談談您將在什麼時候決定選擇哪種策略，並且您有信心無論是哪種策略，都可以準備好並能夠獲得 FDA 批准，大概在 2022 年秋季分發助推器季節，如果這實際上是 2022 年指南中的產品？

And the second question relates to U.S.A. I know previously you had talked about U.S.A. boosting options and purchases. But I can't actually remember what or where we are for U.S.A. for 2022 or for 2023. And maybe just speak to the color about that market.

第二個問題與美國有關。我知道您之前曾談到美國增加期權和購買。但我實際上不記得我們在 2022 年或 2023 年的美國是什麼或在哪裡。也許只是談談那個市場的顏色。

Great, Michael. So I'll take the first question and perhaps turn it over to Stephane for the second. So in terms of the strategy, so the most important thing to start with maybe is that 1273 as a booster already exists. And so that is a booster candidate. Although we're evaluating it as a fourth dose, we'd expect to have that safety data relatively quickly and immunogenicity data, and we've seen strong real-world evidence of mRNA-1273. And so that booster candidate is obviously something that's well known to markets and could be available quite quickly. We're evaluating the Omicron-specific and the Omicron-containing bivalent or 214 in 2 studies that are ongoing right now.

太好了，邁克爾。因此，我將回答第一個問題，也許將第二個問題交給 Stephane。所以就策略而言，最重要的可能是1273作為助推器已經存在。所以這是一個助推器候選人。儘管我們將其作為第四劑進行評估，但我們希望相對較快地獲得安全性數據和免疫原性數據，並且我們已經看到了 mRNA-1273 的強有力的真實證據。因此，助推器候選人顯然是市場眾所周知的東西，並且可以很快獲得。我們正在評估目前正在進行的 2 項研究中的 Omicron 特異性和含有 Omicron 的二價或 214。

Now the challenge with all of that, and I think it's where your question is going, is that when you're trying to evaluate durability -- a difference in durability, that takes time. And so while we're running these studies, both the Omicron and Omicron-containing bivalent, and we expect to have data in the first half of this year that would be 1 month post boost and we could turn around and establish, we believe, the safety and the potential benefit of those boosters and we would hope that the bivalent would continue to be even more compelling, the challenge is that it's going to be very hard to achieve 6 months of durability data before Q3. And that's just a function of time. If you boost people now, it will take time to get that day 181 or 6-month durability data that we've already started to show with our bivalent vaccines.

現在所有這些的挑戰，我認為這就是你的問題所在，當你試圖評估耐久性時——耐久性的差異，這需要時間。因此，當我們進行這些研究時，包括 Omicron 和含有 Omicron 的二價化合物，我們預計今年上半年會有數據，這將是提升後 1 個月的數據，我們可以轉身並建立，我們相信，這些助推器的安全性和潛在好處，我們希望二價將繼續更具吸引力，挑戰在於在第三季度之前實現 6 個月的耐久性數據將非常困難。這只是時間的函數。如果您現在增加人們的數量，則需要時間才能獲得我們已經開始用我們的二價疫苗展示的 181 天或 6 個月的耐用性數據。

And so the question then becomes how do we proceed from a filing perspective if we're aiming at the fall for 2022. And those are consultations that are ongoing with regulators now. We do have the benefit of having tested multiple previous bivalent vaccines, and we do have the benefit of being able to use the 6-month follow-up data there to start to evaluate this potential for better durability. And so you could imagine a world where we proceed with the 1-month data on our bivalent vaccine showing safety and non-inferiority perhaps against the existing variants, including perhaps the circulating variant of concern known as Omicron, and that we follow up over time, perhaps in the early part of the fall, with data that would confirm the improvement in durability. And then we would rely on the fact that the previous bivalent vaccines like mRNA-211 had shown that benefit of durability against previous variants of concern, including some that contain some of the same mutations seen in Omicron.

因此，如果我們的目標是 2022 年秋季，那麼問題就變成瞭如何從備案的角度進行。這些是目前正在與監管機構進行的磋商。我們確實受益於已經測試了多種先前的二價疫苗，並且我們確實受益於能夠使用那裡的 6 個月隨訪數據來開始評估這種提高耐久性的潛力。所以你可以想像這樣一個世界，我們繼續使用我們的二價疫苗的 1 個月數據顯示安全性和非劣效性，可能對現有的變體，包括可能被稱為 Omicron 的關注的循環變體，並且我們會隨著時間的推移進行跟進，也許是在秋季的早些時候，有數據可以證實耐久性的提高。然後我們將依賴這樣一個事實，即以前的二價疫苗（如 mRNA-211）已經證明了對以前關注的變體具有持久性的好處，包括一些包含在 Omicron 中看到的一些相同突變的變體。

And so it's a relatively complicated picture because we all -- we do believe, as we've said, that it is time to update the vaccine against the mutations that are currently circulating and to improve the durability against those new variants of concern, but it does run into the challenge of timing of those filings. And so those consultations with regulators are ongoing, and we'll provide updates as we align with them on the path forward. That's quite different than the public health decision from governments as to which vaccines they may want to prepare to stockpile in advance of a fall booster season, which likely can proceed in parallel even without the regulatory filings as it has in the past as it did during the original first wave of the pandemic.

所以這是一個相對複雜的畫面，因為我們所有人——正如我們所說，我們確實相信，現在是時候針對當前流行的突變更新疫苗並提高針對這些新變種的持久性了，但是它確實遇到了這些文件提交時間的挑戰。因此，與監管機構的磋商正在進行中，我們將在前進的道路上與他們保持一致時提供更新。這與政府做出的公共衛生決定完全不同，即他們可能希望在秋季助推季節之前準備儲備哪些疫苗，即使沒有像過去那樣提交監管文件，這也可能同時進行。最初的第一波大流行。

So with that, maybe I'll turn it over to Stephane to talk about the fall in the U.S.

所以有了這個，也許我會把它交給斯蒂芬來談談美國的墮落。

Thank you, Stephen. So let me maybe talk about it in 2 angles. The first one is, as we've said this morning, in this increased APAs we've announced at $19 billion, there is no signed APA for -- between Moderna and the U.S. government. So the number in there from the U.S. is 0. And because there's no option either that the government has from a previous contract, the U.S. government has no option currently. So there is $0 in the $3 billion of options probabilized.

謝謝你，斯蒂芬。所以讓我從兩個角度來談談。第一個是，正如我們今天早上所說，在我們宣布的 190 億美元的增加的 APA 中，Moderna 和美國政府之間沒有簽署 APA。因此，來自美國的數字是 0。而且由於政府在之前的合同中也沒有選擇權，因此美國政府目前沒有選擇權。因此，在可能的 30 億美元期權中，有 0 美元。

What is not clear today is what would the U.S. government decide to do for the fall of 2022. Will they, like they have done in '20 and '21, buy vaccines from the manufacturers and give them away for free, I believe, for first, second and third dose? Will it be a private market? Or will it be a mix of both private and free vaccine available? Because you could see where we are, if we can sell to private markets, private networks and even companies that might want to procure the vaccines and that's the bit that is not clear. So it is why, in a very conservative manner, because what we have communicated so far are signed APAs or options and because the U.S. government has 0, we did not include any of those numbers.

今天尚不清楚的是，美國政府將決定在 2022 年秋季做什麼。我相信，他們是否會像 20 年和 21 年那樣從製造商那裡購買疫苗並免費贈送第一劑、第二劑和第三劑？會是私人市場嗎？還是會混合使用私人疫苗和免費疫苗？因為你可以看到我們在哪裡，如果我們可以向私人市場、私人網絡甚至可能想要採購疫苗的公司出售，這是不清楚的。這就是為什麼，以非常保守的方式，因為到目前為止我們所傳達的是簽署的 APA 或期權，並且因為美國政府有 0，所以我們沒有包括任何這些數字。

Our next question comes from Cory Kasimov of JPMorgan.

我們的下一個問題來自摩根大通的 Cory Kasimov。

First one, I just want to follow up on what you were just discussing and just kind of looking beyond this fall though and as kind of we think about moving into this endemic phase and how you're thinking it's evolving. Regarding the outlook for the commercial marketplace and like 2023 plus, do you expect APAs for larger countries, be it the U.S. or Europe or anywhere else? Or do you think you'll be doing more selling into private markets? In other words, is there any reason not to shift away from an APA structure?

第一個，我只是想跟進您剛剛討論的內容，並且只是在今年秋天之後展望一下，並且我們考慮進入這個流行階段以及您如何看待它的演變。關於商業市場的前景，比如 2023 年以後，您是否期望更大的國家（無論是美國、歐洲還是其他任何地方）出現 APA？或者你認為你會在私人市場做更多的銷售嗎？換句話說，是否有任何理由不放棄 APA 結構？

And then secondly, just on capital allocation. Recognize your priorities remain the same here, and clearly, with 44 programs in development, new subsidiaries opening around the world, you have enough capital to do many things simultaneously. But how should we think about priorities with nearly 20% of your year-end cash being dedicated to this latest buyback? Is that 15% to 20% range of kind of your balance sheet an appropriate number to be thinking about in the future?

其次，就資本配置而言。認識到你的優先事項在這裡保持不變，很明顯，有 44 個項目正在開發中，新的子公司在世界各地開業，你有足夠的資金同時做很多事情。但是，我們應該如何考慮將您年終現金的近 20% 用於此次最新回購的優先事項？你的資產負債表中 15% 到 20% 的範圍是否是未來需要考慮的合適數字？

So let me take the first question, Cory, and I'll turn to David for the buyback question. So if you look at the countries outside the U.S., they are in, let's say, non-dynamic markets. They are mostly direct contract with governments anywhere. So what it is going to look like in terms of shape and form is not very clear. For example, Europe has purchased together the vaccines for the pandemic, which is not the case, let's say, for seasonal flu, for example. So will they continue that model for COVID and move to that model for other vaccines or would they go back to a national system is to be seen. But all countries like Japan, Canada and so on are basically a single-buyer market. Some countries, there's small private markets but it's mostly kind of government orders.

因此，讓我回答第一個問題，科里，我將轉向大衛的回購問題。因此，如果您查看美國以外的國家/地區，他們處於，比如說，非動態市場。它們大多與任何地方的政府直接簽訂合同。所以它在形狀和形式方面會是什麼樣子還不是很清楚。例如，歐洲已經一起購買了大流行的疫苗，例如季節性流感，情況並非如此。因此，他們是否會繼續採用 COVID 模型並轉向其他疫苗的模型，或者他們是否會回到國家系統，還有待觀察。但日本、加拿大等國家基本上都是單一買家市場。一些國家有小型私人市場，但主要是政府命令。

And so we are in discussions with governments about '23. As you saw, we've already signed contracts for '23 because some countries like the U.K. and others wanted to secure supply because they believe very deeply that the endemic market will require annual boosters. And so we just want to get ahead of it.

因此，我們正在與政府討論 23 年。正如你所看到的，我們已經簽署了 23 年的合同，因為一些國家（如英國）和其他一些國家希望確保供應，因為他們非常相信地方性市場將需要每年的助推器。所以我們只想領先一步。

And as you saw with what we are doing with Canada and Australia, which I think is a very interesting new model of kind of service-based, subscription-like partnership, is we basically are trying to secure, as we said, 10-year agreements. And we're in discussion with several more countries about setting the similar model in the countries where we build a plant. They will reserve a given volume for a year, let's say, $20 million, $50 million, $100 million, depending on the market size. And then what we commit to them is to be able to customize the respiratory vaccines with what they believe they want.

正如你所看到的，我們與加拿大和澳大利亞正在做的事情，我認為這是一種非常有趣的基於服務、類似訂閱的合作夥伴關係的新模式，我們基本上是在努力確保，正如我們所說，10 年協議。我們正在與其他幾個國家討論在我們建廠的國家建立類似的模式。根據市場規模，他們將保留給定數量的一年，例如 2000 萬美元、5000 萬美元、1 億美元。然後，我們向他們承諾的是能夠根據他們認為自己想要的方式定制呼吸道疫苗。

So as you saw from Paul's presentation, there's a lot of respiratory virus that most people are not aware of even their names. Look at PIV. Very few people knew that there were coronaviruses circulating and creating so much hospitalization and deaths every year. Well, our vision is to bring all of those components together and discuss with local public health experts, on an annual basis, what do they want in their vaccine for Canada or vaccine for Australia.

所以正如你從保羅的演講中看到的，有很多呼吸道病毒，大多數人甚至都不知道他們的名字。看看PIV。很少有人知道有冠狀病毒在傳播並每年造成如此多的住院和死亡。好吧，我們的願景是將所有這些組成部分整合在一起，並每年與當地公共衛生專家討論他們在加拿大疫苗或澳大利亞疫苗中的需求。

As we discussed on the flu call in the fall, sometimes, WHO picks a flu strain like H3, or -- and then it's a different flu strain that winter that is between, let's say, North America, Europe and/or Asia, like Japan and so on. And so this ability to also customize and -- work with local public health authorities to customize a vaccine they want, we think it's a really unique feature of this platform because of the speed, because of ability to combine components.

正如我們在秋季流感電話會議上討論的那樣，有時，世衛組織會選擇 H3 之類的流感病毒株，或者 - 然後是那個冬天介於北美、歐洲和/或亞洲之間的另一種流感病毒株，比如日本等。因此，這種定制能力以及與當地公共衛生當局合作定制他們想要的疫苗的能力，我們認為這是該平台的一個真正獨特的功能，因為它具有速度和組合組件的能力。

And so that's what we're already trying to do here, is to really establish very long-term agreements. I am not aware of other companies having done this type of agreement in pharma. And I think this is something we can do and that the teams are working very actively also. We'll have to wait a few more months to see more coming, but there are quite a lot of discussion. We just have to wait for that because we cannot do 10 countries at the same time in discussion because they are very customized and very complex partnerships. But that's exactly where we're trying to go ahead.

所以這就是我們已經在這裡嘗試做的，是真正建立非常長期的協議。我不知道其他公司已經在製藥領域達成了此類協議。我認為這是我們可以做的事情，並且團隊也非常積極地工作。我們將不得不再等幾個月才能看到更多的消息，但有很多討論。我們只需要等待，因為我們不能同時討論 10 個國家，因為它們是非常定制和非常複雜的伙伴關係。但這正是我們努力前進的方向。

David, do you want to talk about our thinking about buybacks?

大衛，你想談談我們對回購的想法嗎？

Sure, yes. Yes. I mean, I guess what I'd say about the announcement today, I think what you need to think about is a few things as we did. So why $3 billion? Why now? It starts with a few things. One is, as we said, investing internally and externally and ensuring that we have plenty of firepower to allow us to do that. So clearly, where we enter 2022, we're in a good position to fund all of the opportunities that we think we have and they're very compelling. So that's one.

當然，是的。是的。我的意思是，我想我要對今天的公告說些什麼，我認為你需要考慮的是我們所做的一些事情。那麼為什麼要 30 億美元呢？為什麼現在？它從幾件事開始。正如我們所說，其中之一是在內部和外部進行投資，並確保我們有足夠的火力來做到這一點。很明顯，在我們進入 2022 年的地方，我們處於有利位置，可以為我們認為擁有的所有機會提供資金，而且這些機會非常引人注目。所以這是一個。

Two is looking at what visibility we have of additional cash generation for the company. And again, we feel very good about that certainly as we enter 2022. And then thirdly, we look at the valuation levels, and certainly, we think this is quite attractive at these levels. So combination of all that adds up to an announcement of $3 billion.

二是查看我們對公司額外現金產生的可見性。再一次，當我們進入 2022 年時，我們對此肯定感覺非常好。然後第三，我們看看估值水平，當然，我們認為這在這些水平上非常有吸引力。因此，所有這些加起來就是 30 億美元的公告。

To your question, should I be filling in the model for that to continue on an ongoing basis? I think it's a little bit early for us to comment right now on that question. And I'd encourage you just to wait and let's see how this evolves. But we feel very good about the prospects for the business. I think the statement today is one of a strong confidence that we can achieve all of the objectives that we've set out for the company.

對於您的問題，我是否應該填寫模型以持續進行？我認為我們現在就這個問題發表評論還為時過早。我鼓勵你等待，讓我們看看它是如何演變的。但我們對這項業務的前景感覺非常好。我認為今天的聲明是我們能夠實現我們為公司設定的所有目標的堅定信心之一。

Our last question comes from Tyler Van Buren with Cowen.

我們的最後一個問題來自 Tyler Van Buren 和 Cowen。

On a similar topic of conversation, can you just provide your latest thoughts on future U.S. pricing for Spikevax? Do you expect future contracts to have pricing that has normalized relative to ex-U.S. countries?

關於類似的話題，您能否提供您對 Spikevax 未來美國定價的最新想法？您是否期望未來合同的定價相對於美國以外地區已經正常化？國家？

And maybe just on a second point to clarify. Do you believe that a new variant wave emerging by year-end is necessary to record the vast majority of the $3 billion in APA options?

也許只是在第二點要澄清。您是否認為有必要在年底出現新的變體浪潮來記錄 30 億美元 APA 期權中的絕大多數？

So let me start. So I will not comment on the U.S. pricing for obvious reasons, because of our discussions with the government. I think as we said before, once this goes into normal private market, we do expect the pricing to be higher. We think the vaccine does not reflect -- sorry, the price doesn't reflect the value of a vaccine from a pharmacoeconomic standpoint.

那麼讓我開始吧。因此，由於我們與政府進行了討論，出於顯而易見的原因，我不會對美國的定價發表評論。我認為正如我們之前所說，一旦進入正常的私人市場，我們確實預計定價會更高。我們認為疫苗沒有反映——抱歉，從藥物經濟學的角度來看，價格並沒有反映疫苗的價值。

And I mean the options, the $3 billion, so they are just different stage. Some are just waiting funding from governments to move into fully signed APAs. Some are things with COVAX that has placed orders for future needs. So I don't think there needs to be a new variant for some of it to happen and plus the U.S. on top of that.

我的意思是選項，30 億美元，所以它們只是不同的階段。有些人只是在等待政府提供資金以進入完全簽署的預約定價安排。有些是 COVAX 為未來需求下訂單的東西。所以我認為不需要有一個新的變種來實現其中的一些，再加上美國。

But again, we have never managed through a pandemic and through a transition from pandemic to endemic. So otherwise, we want to be cautious and prudent. But I think it doesn't need a new variant for a material chunk of the $3 billion to move into signed APAs.

但同樣，我們從未經歷過大流行以及從大流行到地方病的轉變。因此，否則，我們要謹慎和謹慎。但我認為，將 30 億美元中的很大一部分轉移到簽署的 APA 中並不需要新的變體。

Ladies and gentlemen, this concludes the Q&A portion of today's conference. I'd like to turn the call back to Stephane for any closing remarks.

女士們，先生們，今天會議的問答部分到此結束。我想將電話轉回給 Stephane 以獲取任何結束語。

Well, thank you very much everybody for joining. I look forward to talking to you in the coming days and weeks and especially to welcome you at our Vaccine Day, which will be exciting, in March. Thank you.

嗯，非常感謝大家的加入。我期待在接下來的幾天和幾週內與您交談，特別是在三月的疫苗日歡迎您，這將是令人興奮的。謝謝你。

Ladies and gentlemen, this does conclude today's presentation. You may now disconnect, and have a wonderful day.

女士們，先生們，今天的演講到此結束。您現在可以斷開連接，度過美好的一天。