Vaxcyte Inc (PCVX) 2022 Q4 法說會逐字稿

Good afternoon. My name is Lisa, and I will be your conference operator today. At this time, I would like to welcome everyone to the Vaxcyte Fourth Quarter and Full Year 2022 Financial Results Conference Call. (Operator Instructions)

下午好。我叫麗莎，今天我將擔任你們的會議接線員。此時，我想歡迎大家參加 Vaxcyte 第四季度和 2022 年全年財務業績電話會議。 （操作員說明）

I now would like to turn the call over to Andrew Guggenhime, President and Chief Financial Officer of Vaxcyte. Please go ahead, sir.

我現在想把電話轉給 Vaxcyte 總裁兼首席財務官 Andrew Guggenhime。請繼續，先生。

Thank you, operator, and good afternoon, everyone. I'd like to welcome you to Vaxcyte's earnings conference call to discuss our 2022 results and to provide a business update. I am joined today by our Chief Executive Officer, Grant Pickering; our EVP and Chief Operating Officer, Jim Wassil; and our VP of Research, Jeff Fairman.

謝謝接線員，大家下午好。歡迎您參加 Vaxcyte 的收益電話會議，討論我們 2022 年的業績並提供業務更新。今天，我們的首席執行官格蘭特·皮克林 (Grant Pickering) 加入了我的行列；我們的執行副總裁兼首席運營官 Jim Wassil；以及我們的研究副總裁 Jeff Fairman。

Earlier this afternoon, we issued a news release announcing our results. Copies of this and our other news releases, latest corporate presentation and SEC filings can be found in the Investors and Media section of our website.

今天下午早些時候，我們發布了一份新聞稿，宣布了我們的結果。可以在我們網站的投資者和媒體部分找到本新聞稿和我們的其他新聞稿、最新的公司介紹和 SEC 文件的副本。

Before we begin, I'd like to remind you that during this call, we'll be making certain forward-looking statements about Vaxcyte, which are subject to various risks, uncertainties and other factors that could cause actual results to differ materially from those referred to in any forward-looking statements. For a discussion of the risks and uncertainties associated with these statements, please see our press release issued today as well as our most recent filings with the SEC, including the risk factors set forth in our Form 10-K for the year ended December 31, 2022, and any subsequent reports filed with the SEC.

在我們開始之前，我想提醒您，在本次電話會議期間，我們將對 Vaxcyte 做出某些前瞻性陳述，這些陳述受到各種風險、不確定性和其他因素的影響，這些因素可能導致實際結果與那些結果大不相同在任何前瞻性陳述中提及。有關與這些聲明相關的風險和不確定性的討論，請參閱我們今天發布的新聞稿以及我們最近向美國證券交易委員會提交的文件，包括我們截至 12 月 31 日的 10-K 表格中規定的風險因素， 2022 年，以及向 SEC 提交的任何後續報告。

With that, I'll turn the call over to Grant Pickering. Grant?

有了這個，我會把電話轉給格蘭特皮克林。授予？

Thank you, Andrew. And to all of you on the call and webcast, thanks for joining us today. 2022 is a landmark year for Vaxcyte. We reported positive and unprecedented proof-of-concept top line clinical data for VAX-24, our lead pneumococcal conjugate vaccine for the prevention of invasive pneumococcal disease in adults. These remarkable data validate our PCV franchise and our carrier-sparing approach for broad-spectrum PCVs as well as our sell-through platform.

謝謝你，安德魯。對於所有參加電話會議和網絡廣播的人，感謝您今天加入我們。 2022年對於Vaxcyte來說是具有里程碑意義的一年。我們報告了 VAX-24 的正面和前所未有的概念驗證頂線臨床數據，VAX-24 是我們用於預防成人侵襲性肺炎球菌疾病的主要肺炎球菌結合疫苗。這些卓越的數據驗證了我們的 PCV 特許經營權和我們的廣譜 PCV 運營商備用方法以及我們的銷售平台。

They also represent the culmination of nearly a decade of thoughtful and methodical research and development by the entire Vaxcyte team and our partners. The findings of the large Phase II study in adults 18 to 64 years of age indicate a potential best-in-class profile for VAX-24 and demonstrate how our novel cell-free technology platform has the capability to overcome the limitations of other conventional approaches.

它們還代表了整個 Vaxcyte 團隊和我們的合作夥伴近十年來深思熟慮和有條不紊的研究和開發的結晶。對 18 至 64 歲成人進行的大型 II 期研究的結果表明 VAX-24 具有潛在的同類最佳特徵，並展示了我們的新型無細胞技術平台如何能夠克服其他傳統方法的局限性.

These results and the foundation we have carefully created have us well positioned to advance our PCV franchise to potentially disrupt what has consistently been a crucial vaccine class societally and financially. I'm incredibly proud of the progress this past year, and I'm optimistic about our ability to execute and further scale our business in 2023 and beyond.

這些結果和我們精心創建的基礎使我們能夠很好地推進我們的 PCV 特許經營權，以潛在地破壞在社會和經濟上一直是至關重要的疫苗類別。我為過去一年取得的進展感到無比自豪，我對我們在 2023 年及以後執行和進一步擴展業務的能力感到樂觀。

As we look ahead, we remain focused on advancing both of our PCV franchise programs, VAX-24 and VAX-31, which we previously referred to as VAX-XP, with several upcoming milestones. VAX-24, our lead PCV candidate, was recently granted Breakthrough Therapy Designation for adults, adding to its Fast Track Designation, and we remain on track to deliver top line safety, tolerability and immunogenicity results in subjects 65 and older in the second quarter of this year.

展望未來，我們將繼續專注於推進我們的 PCV 特許經營計劃 VAX-24 和 VAX-31（我們之前稱為 VAX-XP），並實現幾個即將到來的里程碑。 VAX-24，我們的主要 PCV 候選藥物，最近被授予成人突破性治療指定，增加了其快速通道指定，我們仍然有望在第二季度為 65 歲及以上的受試者提供頂級安全性、耐受性和免疫原性結果今年。

As we've discussed with many of you, for this pending readout, our focus from an immunogenicity perspective is almost exclusively on the point estimates for the OPA geometric mean ratios, or GMRs, and their comparability to the prior results in our much larger Phase II study in younger adults. Given the smaller size of this older adult trial at 50 subjects per cohort, these point estimate GMRs are the most important focal point and not the lower bounds of the confidence intervals. This study was not powered to meet the regulatory noninferiority standard, and as a result, these confidence intervals will be substantially wider.

正如我們與你們中的許多人討論的那樣，對於這個待定的讀數，我們從免疫原性的角度關注的重點幾乎完全放在 OPA 幾何平均比率或 GMR 的點估計上，以及它們與我們更大階段的先前結果的可比性II 研究年輕人。鑑於這項老年試驗的規模較小，每個隊列 50 名受試者，這些點估計 GMR 是最重要的焦點，而不是置信區間的下限。這項研究的功效不足以滿足監管的非劣效性標準，因此，這些置信區間將大大擴大。

The combined data from both adult Phase II studies will enable us to perform the statistical powering necessary to tee up our pivotal Phase III noninferiority study for VAX-24 in adults. These data, along with the full 6-month safety data from both studies, will facilitate our end of Phase II meeting with FDA, which we expect to hold in the second half of this year.

來自兩項成人 II 期研究的綜合數據將使我們能夠執行必要的統計分析，為我們針對成人 VAX-24 的關鍵性 III 期非劣效性研究做好準備。這些數據以及兩項研究的完整 6 個月安全數據將有助於我們結束與 FDA 的 II 期會議，我們預計該會議將於今年下半年舉行。

To put the U.S. adult PCV market opportunity in the context, today, it is approximately $2 billion of the $7 billion total annual global market and is expected to be the fastest-growing segment of the market going forward. Key growth drivers include an increase in adult vaccination rates outside the U.S., and in the U.S., the potential shift to universal adult vaccination starting at age 50 instead of age 65, which itself would expand the market and open up the adult regimen to a prime-boost schedule, as is the case in the input market.

將美國成人 PCV 市場機會放在背景中，今天，它在 70 億美元的年度全球市場總額中約佔 20 億美元，預計將成為未來增長最快的市場部分。主要增長動力包括美國以外成人疫苗接種率的提高，以及在美國，成人疫苗接種可能從 50 歲開始從 65 歲開始轉變，這本身將擴大市場並使成人方案達到最佳水平-升壓計劃，就像輸入市場的情況一樣。

The infant cohort represents the largest portion of the global pneumococcal vaccine market with approximately $5 billion in annual sales, and we are thrilled to be launching our first clinical program in infants in the second quarter of this year. This follows FDA clearance of our IND application, which we announced last week. Bringing the broadest PCV to both infants and adults represents an opportunity to significantly reduce invasive disease across the entire population.

嬰兒隊列佔全球肺炎球菌疫苗市場的最大部分，年銷售額約為 50 億美元，我們很高興能在今年第二季度啟動我們的第一個嬰兒臨床項目。這是繼 FDA 批准我們上周宣布的 IND 申請之後。為嬰兒和成人提供最廣泛的 PCV 意味著有機會顯著減少整個人群的侵襲性疾病。

To maintain a long-term leadership position in this market, and to address the serotype replacement phenomenon that we would expect based on the widespread use of the 24-valent PCV, we continued to invest in our 31-valent VAX-31 program. Similar to VAX-24, we believe our unique carrier-sparing PCV approach gives us the opportunity to expand the spectrum of coverage to address additional pathogenic serotypes without compromising the ability to continue to vaccinate against previously circulating strains.

為了保持在該市場的長期領先地位，並解決我們預期的基於 24 價 PCV 廣泛使用的血清型替代現象，我們繼續投資於我們的 31 價 VAX-31 計劃。與 VAX-24 類似，我們相信我們獨特的保留攜帶者 PCV 方法使我們有機會擴大覆蓋範圍以解決其他致病性血清型，而不會影響繼續接種先前流行菌株的能力。

This is critical since previously controlled strains have rebounded in prior instances where vaccine coverage was withdrawn. This puts Vaxcyte in a different position than other sponsors who are applying the conventional PCV approach and are forced to make sacrifices in an attempt to cover newly circulating strains.

這是至關重要的，因為在先前取消疫苗覆蓋範圍的情況下，先前控制的菌株已經反彈。這使得 Vaxcyte 與其他應用傳統 PCV 方法並被迫做出犧牲以試圖覆蓋新流行菌株的讚助商處於不同的位置。

We have continued to make significant investments in the advancement of VAX-31 and expect to submit the adult IND for this program in the second half of this year and deliver top line data next year.

我們繼續對 VAX-31 的進步進行大量投資，並預計在今年下半年提交該項目的成人 IND，並在明年提供頂級數據。

Beyond our PCV franchise, we continue to progress and bolster our early-stage pipeline of novel vaccines, including VAX-31, a conjugate vaccine candidate designed to prevent infections in both adults and children caused by Group A Strep bacteria. And VAX-PG, which is designed to treat periodontal disease.

除了我們的 PCV 特許經營權之外，我們繼續推進和加強我們的新型疫苗的早期管道，包括 VAX-31，這是一種結合疫苗候選物，旨在預防成人和兒童由 A 組鏈球菌引起的感染。以及專為治療牙周病而設計的 VAX-PG。

We are also introducing a new program called VAX-GI, a vaccine designed to prevent shigella, a danger bacterial infection with significant fatality rates among infants in low- and middle-income settings. Jeff will provide additional details on our earlier-stage programs later on today's call.

我們還推出了一項名為 VAX-GI 的新計劃，這是一種旨在預防志賀氏菌的疫苗，志賀氏菌是一種危險的細菌感染，在中低收入地區的嬰兒中死亡率很高。 Jeff 將在今天的電話會議晚些時候提供有關我們早期項目的更多詳細信息。

Given the magnitude of the opportunity for our PCV franchise, we continue to invest to further solidify our manufacturing foundation. Our strategic relationship with Lonza remains strong, and we believe we are well positioned to support a potential adult VAX-24 launch in the U.S. market out of existing Lonza facilities. Plans to ensure and expanded commercial manufacturing footprint to support the infant indication in an ex U.S. markets are underway. Additionally, we further fortified our extract supply chain via our recent expanded agreement with Sutro Biopharma.

鑑於我們的 PCV 特許經營機會巨大，我們將繼續投資以進一步鞏固我們的製造基礎。我們與龍沙的戰略關係依然牢固，我們相信我們有能力支持在美國市場利用現有的龍沙設施推出潛在的成人 VAX-24。確保和擴大商業製造足跡以支持美國前市場嬰兒適應症的計劃正在進行中。此外，我們通過最近與 Sutro Biopharma 的擴展協議進一步加強了我們的提取物供應鏈。

From a financial perspective, we are in a strong position with over $950 million on the balance sheet as of December 31, aided by 2 successful follow-on financing last year totaling $805 million in gross proceeds. This financial strength provides us the capital to fund through several important incremental milestones, which Andrew will highlight later.

從財務角度來看，截至 12 月 31 日，我們的資產負債表上有超過 9.5 億美元，這得益於去年 2 次成功的後續融資，總收益為 8.05 億美元。這種財務實力為我們提供了通過幾個重要的增量里程碑提供資金的資金，安德魯將在稍後重點介紹。

I'll now turn it over to Jim, who will provide more details on our PCV programs. Jim?

我現在將其轉交給 Jim，他將提供有關我們 PCV 計劃的更多詳細信息。吉姆？

Thanks, Grant. I'd like to start by reiterating why developing broader coverage vaccines to treat pneumococcal disease matters. Despite widespread administration of effective vaccines, the global impact of disease remains significant and is associated with high-case fatality rates, antibiotic resistance and meningitis.

謝謝，格蘭特。我想首先重申為什麼開發覆蓋面更廣的疫苗來治療肺炎球菌疾病很重要。儘管廣泛使用了有效疫苗，但疾病的全球影響仍然很大，並且與高病死率、抗生素耐藥性和腦膜炎有關。

In the U.S. alone, adult and the pediatric pneumococcal vaccines only cover approximately 60% and 41%, respectively, of circulating disease. As a result, the public health community continues to affirm the need for broader spectrum vaccines to prevent invasive disease or IPD. we've designed VAX-24 to deliver a PCV that includes all of the serotypes covered by the currently marketed vaccines.

僅在美國，成人和兒童肺炎球菌疫苗分別只覆蓋了大約 60% 和 41% 的循環疾病。因此，公共衛生界繼續確認需要更廣譜的疫苗來預防侵襲性疾病或 IPD。我們設計了 VAX-24 來提供一種 PCV，該 PCV 包括當前上市疫苗所涵蓋的所有血清型。

As confirmed by our strong clinical results from the Phase I/II proof-of-concept study, VAX-24 has the potential to provide an additional 10% to 28% of protection for adults compared with the standard of care PCVs. In this study, VAX-24 met the approval noninferiority threshold for all 24 serotypes and exceeded the immune response of PCV20 for 16 of the common 20 serotypes. 4 of those demonstrated statistically superior responses.

正如我們來自 I/II 期概念驗證研究的強大臨床結果所證實的那樣，與標準護理 PCV 相比，VAX-24 有可能為成人提供額外 10% 至 28% 的保護。在這項研究中，VAX-24 達到了所有 24 种血清型的批准非劣效性閾值，並且超過了 PCV20 對 20 種常見血清型中的 16 種的免疫反應。其中 4 個在統計上表現出更好的反應。

Based on these results, we believe we have the opportunity to set a new bar for the pneumococcal vaccine by delivering broader coverage and higher immune responses relative to the conventional PCV. Looking ahead, we expect top line data for our second Phase II study in adults 65 and older in the second quarter of this year. With the upcoming second quarter data readout, I want to provide a bit more context about our objectives and the expectations for this study.

基於這些結果，我們相信我們有機會通過提供比傳統 PCV 更廣泛的覆蓋範圍和更高的免疫反應來為肺炎球菌疫苗設立新的標準。展望未來，我們預計今年第二季度我們針對 65 歲及以上成年人的第二階段 II 研究的頂級數據。隨著即將公佈的第二季度數據，我想提供更多關於我們的目標和對這項研究的期望的背景信息。

As a reminder, the study design is identical to the first Phase II study, but for the age and the number of subjects at 50 subjects per cohort versus nearly 200 in the first Phase II study. This smaller study was designed to further inform the powering of the pivotal Phase III study, while adding to the body of research for VAX-24. As Grant mentioned, it was not powered to demonstrate noninferiority. So it is most important to focus on the point estimates for the OPA-geometric mean ratios for each of the serotypes rather than the confidence interval.

提醒一下，該研究設計與第一項 II 期研究相同，但在年齡和受試者數量方面，每個隊列 50 名受試者，而第一項 II 期研究中有近 200 名受試者。這項較小的研究旨在進一步為關鍵的 III 期研究提供動力，同時增加 VAX-24 的研究主體。正如格蘭特所提到的，它無力證明非劣效性。因此，最重要的是關注每种血清型的 OPA 幾何平均比率的點估計，而不是置信區間。

That's because you can expect these confidence intervals to be wider, and it's very possible that several may cross the 0.5 noninferiority threshold. Yet, if the GMRs are between 0.6 to 0.75 or higher for each serotype, prior Phase III studies have shown that these ratios are adequate to achieve the noninferiority threshold. We can glean some useful insights when looking at the results of the age stratification analysis of the first Phase II study as seen on Slide 12.

這是因為您可以預期這些置信區間會更寬，並且很可能有幾個可能會超過 0.5 的非劣效性閾值。然而，如果每种血清型的 GMR 在 0.6 到 0.75 之間或更高，之前的 III 期研究表明這些比率足以達到非劣效性閾值。在查看第一個 II 期研究的年齡分層分析結果（如幻燈片 12 所示）時，我們可以收集到一些有用的見解。

The graph to the left reflects the data we shared in October of last year from the full study population, in which the confidence intervals for the OPA GMRs were relatively narrow. The 2 additional forest plots show the 8 stratified OPA GMRs. In the 60- to 64-year-old cohort, shown on the far right of this slide, we had approximately 50 subjects. The results show a general improvement in the point estimates, which is encouraging and, as expected, a significant widening of the conference intervals due to the smaller sample size.

左圖反映了我們在去年 10 月分享的全部研究人群的數據，其中 OPA GMR 的置信區間相對較窄。 2 個額外的森林圖顯示了 8 個分層的 OPA GMR。在本幻燈片最右側顯示的 60 至 64 歲人群中，我們有大約 50 名受試者。結果顯示點估計的普遍改善，這是令人鼓舞的，並且正如預期的那樣，由於樣本量較小，會議間隔顯著擴大。

These confidence intervals are relevant because we enrolled approximately the same number of subjects per cohort in the 65-and-older study. When we announced our top line data from the older adult study, given precedent Phase III programs have enrolled subjects both older and younger than 65. We also plan to share pooled data that includes the results from the 60- to 64-year-old cohort in our prior study.

這些置信區間是相關的，因為我們在 65 歲及以上的研究中每個隊列招募了大約相同數量的受試者。當我們公佈老年人研究的頂線數據時，鑑於先例 III 期計劃招募了 65 歲以下和 65 歲以下的受試者。我們還計劃共享包括 60 至 64 歲隊列結果的匯總數據在我們之前的研究中。

Based on well-established development pathways, we anticipate the Phase III study design will include the same validated surrogate immune endpoints that have served as the basis for full approval of multiple prior PCVs. These were also the basis for our positive Phase II study. We expect top line data from that pivotal Phase III noninferiority study in 2025, and we will keep you apprised of other milestones following the planned regulatory interactions in the second half of this year.

基於既定的開發途徑，我們預計 III 期研究設計將包括相同的經過驗證的替代免疫終點，這些終點已作為完全批准多個先前 PCV 的基礎。這些也是我們積極的 II 期研究的基礎。我們預計 2025 年關鍵的 III 期非劣效性研究將獲得一線數據，我們將讓您了解今年下半年計劃的監管互動之後的其他里程碑。

As our adult program advances, we are also excited to move into the infant population with VAX-24 and plan to initiate a Phase II study in the second quarter of this year. This study, outlined on Slide 13, includes 3 doses given to healthy infants in the first 6 months of life. This is referred to as the primary series. Primary series is followed by a dose administered at 12 to 15 months of age, which is referred to as the booster dose.

隨著我們成人項目的推進，我們也很高興能夠將 VAX-24 用於嬰兒人群，併計劃在今年第二季度啟動 II 期研究。幻燈片 13 概述了這項研究，包括在生命的頭 6 個月內給健康嬰兒注射的 3 劑疫苗。這被稱為主要係列。初級系列之後是在 12 至 15 個月大時給予的劑量，這被稱為加強劑量。

This study will be conducted in 2 stages, and we will compare VAX-24 to the broadest standard-of-care PCV, which today is PCV15. The stage 1 portion of the study will evaluate the safety and tolerability of a single injection of VAX-24 at 3-dose levels compared to PCV15 in approximately 48 infants at 2 months of age in a dose-escalation manner. Participants will be randomized on a 3:1 basis and will be evaluated for safety at 7 days after dosing. A data safety monitoring committee will evaluate these data, to which we will remain blinded before making a go/no-go decision to enable us to proceed to a higher dose and ultimately to the second stage of the study.

這項研究將分兩個階段進行，我們會將 VAX-24 與最廣泛的護理標準 PCV（今天是 PCV15）進行比較。該研究的第 1 階段部分將以劑量遞增的方式在大約 48 名 2 個月大的嬰兒中評估與 PCV15 相比單次注射 3 劑量水平的 VAX-24 的安全性和耐受性。參與者將以 3:1 的比例隨機分配，並將在給藥後 7 天評估安全性。數據安全監測委員會將評估這些數據，在做出通過/不通過決定之前，我們將對這些數據保持盲態，以使我們能夠繼續進行更高劑量並最終進入研究的第二階段。

The second stage of the study is significantly larger and will enroll approximately 750 healthy infants. We will evaluate safety, tolerability and immunogenicity for the same 3 doses of VAX-24 and compared to PCV15. Participants will be randomized equally into 4 separate arms, with serology drawn for immunogenicity evaluations at 7 months and before and after the booster dose.

第二階段的研究規模要大得多，將招募大約 750 名健康嬰兒。我們將評估相同 3 劑 VAX-24 的安全性、耐受性和免疫原性，並與 PCV15 進行比較。參與者將被平均隨機分配到 4 個獨立的組中，在 7 個月和加強劑之前和之後抽取血清學進行免疫原性評估。

The key prespecified immunogenicity study endpoints will follow convention, which includes an assessment of the percent of participants with IgG titers above predefined levels after the primary series and the IgG geometric mean concentrations after the booster dose, both of which will be compared to PCV15 for the common serotypes. We expect top line data from this study following the primary 3-dose immunization series by 2025, with the top line data from the booster dose to come later.

關鍵的預先指定的免疫原性研究終點將遵循慣例，其中包括評估初級系列後 IgG 滴度高於預定水平的參與者百分比和加強劑量後的 IgG 幾何平均濃度，兩者都將與 PCV15 進行比較常見血清型。我們預計到 2025 年，這項研究將在 3 劑初級免疫接種系列之後獲得頂線數據，而來自加強劑量的頂線數據將在稍後公佈。

As Grant noted, we also continue to advance VAX-31, our 31-valent PCV candidate designed to provide coverage of approximately 95% of the IPD currently circulating in the U.S. adult population. We've now identified the additional 7 serotypes included in VAX-31 beyond the 24 serotypes in VAX-24 and believe this breadth of coverage goes beyond any other PCV in development. We are completing IND-enabling activities and intend to submit the adult IND in the second half of this year.

正如 Grant 指出的那樣，我們還繼續推進 VAX-31，這是我們的 31 價 PCV 候選藥物，旨在覆蓋目前在美國成年人群中傳播的大約 95% 的 IPD。除了 VAX-24 中的 24 种血清型，我們現在已經確定了 VAX-31 中包含的另外 7 种血清型，並且相信這種覆蓋範圍超過了任何其他正在開發的 PCV。我們正在完成 IND 授權活動，並打算在今年下半年提交成人 IND。

With that, I'll turn it over to Jeff to provide an update on our early-stage program. Jeff?

有了這個，我會把它交給 Jeff 來提供我們早期計劃的更新。傑夫？

Thanks, Jim. In addition to our PCV franchise, we also have a robust earlier-stage pipeline, for which we continue to leverage our cell-free platform. VAX-A1, our novel conjugate vaccine designed to prevent infections caused by Group A Strep, remains highly relevant given the recent outbreaks that have captured news headlines. Group A Strep is one of the leading infectious disease-related causes of death and disability worldwide and is a significant contributor to the prescription of antibiotic in the very young.

謝謝，吉姆。除了我們的 PCV 特許經營權外，我們還有一個強大的早期管道，為此我們繼續利用我們的無細胞平台。 VAX-A1 是我們旨在預防由 A 組鏈球菌引起的感染的新型結合疫苗，鑑於最近的疫情已成為新聞頭條，它仍然具有高度相關性。 A 組鏈球菌是世界範圍內導致死亡和殘疾的主要傳染病相關原因之一，並且是非常年輕的抗生素處方的重要貢獻者。

IND-enabling activities continue as VAX-A1 advances to the clinic. These include analytical assay method development, immunological assays and scaling up the processes towards the production of GMP-grade drug substance and drug product. We will give updates as to the anticipated timing of the IND submission as the program advances.

隨著 VAX-A1 進入臨床，支持 IND 的活動仍在繼續。這些包括分析測定方法開發、免疫學測定和擴大生產 GMP 級原料藥和藥品的過程。隨著項目的推進，我們將更新 IND 提交的預期時間。

I'm also pleased to share that we have achieved our goal last year to name a final candidate for VAX-PG, our therapeutic vaccine candidate designed to treat periodontal disease. Periodontal disease impacts approximately 65 million adults in the U.S., resulting in productivity losses that are estimated at more than $50 billion per year. As we await the readout of our final preclinical studies, we have begun the scale up of the production of our candidate vaccine proteins, analytical assay development and clinical serology assay development necessary to support eventual early-stage clinical studies.

我也很高興與大家分享，我們去年已經實現了我們的目標，即為 VAX-PG 指定最終候選疫苗，這是我們設計用於治療牙周病的治療性疫苗候選疫苗。牙周病影響了美國大約 6500 萬成年人，造成的生產力損失估計每年超過 500 億美元。在我們等待最終臨床前研究的結果時，我們已經開始擴大候選疫苗蛋白的生產、分析檢測開發和臨床血清學檢測開發，以支持最終的早期臨床研究。

VAX-PG leverages a key application of our cell-free platform, which is the ability to make tough to make protein antigens. This also has a bearing on the nomination of our new vaccine program, VAX-GI. VAX-GI is designed to prevent dysentery caused by shigella bacteria, which is commonly referred to as shigellosis. Shigellosis is a bacterial illness with no available preventive treatment. It affects an estimated 188 million people worldwide each year and results in approximately 164,000 deaths annually, mostly among children under 5 years of age in low- and middle-income areas. With the aim of reducing morbidity and mortality due to this disease, the WHO lists Shigella vaccine development as a priority goal. More information can be seen on Slide 17.

VAX-PG 利用了我們無細胞平台的一個關鍵應用，即製造蛋白質抗原的能力。這也與我們新疫苗計劃 VAX-GI 的提名有關。 VAX-GI 旨在預防志賀氏菌引起的痢疾，通常稱為志賀氏菌病。志賀氏菌病是一種細菌性疾病，沒有可用的預防性治療方法。據估計，它每年影響全世界 1.88 億人，每年導致約 164,000 人死亡，其中大多數是中低收入地區 5 歲以下的兒童。為了降低這種疾病的發病率和死亡率，世界衛生組織將開發志賀氏菌疫苗列為優先目標。可以在幻燈片 17 上看到更多信息。

The central antigen in VAX-GI is Epa B. While this is a well-appreciated antigen, others have been unable to produce Epa B at an amount sufficient to enable a commercial product. Yet with our cell-free technology, we believe we can produce this antigen at substantially improved yields, allowing for commercial scale production. More information on this unique application of the cell-free technology is available in the Publication section of our website. We look forward to sharing more updates on our earlier-stage pipeline as the year progresses.

VAX-GI 中的中心抗原是 Epa B。雖然這是一種廣受認可的抗原，但其他抗原無法以足以實現商業產品的量生產 Epa B。然而，憑藉我們的無細胞技術，我們相信我們能夠以顯著提高的產量生產這種抗原，從而實現商業規模生產。有關無細胞技術這一獨特應用的更多信息，請訪問我們網站的“出版物”部分。隨著時間的推移，我們期待分享更多關於我們早期管道的更新。

I would now like to turn the call over to Andrew, who will provide a financial update.

我現在想把電話轉給安德魯，他將提供財務更新。

Thanks, Jeff. I'll briefly cover a few financial points, before turning it over to Grant for our closing remarks. With respect to the income statement, the details of our fourth quarter and year-end 2022 results and the reasons for the variances to the comparable 2021 periods are reflected in our 10-K filing and summarized in our press release.

謝謝，傑夫。在將它交給格蘭特作我們的結束語之前，我將簡要介紹幾個財務要點。關於損益表，我們的 10-K 文件中反映了我們 2022 年第四季度和年底業績的詳細信息以及與 2021 年可比期間差異的原因，並在我們的新聞稿中進行了總結。

The year-over-year increase in R&D expenses was due primarily to higher manufacturing and clinical development expenses for VAX-24 as we invested to prepare for the planned Phase III clinical trials and initiated and completed enrollment in 2 Phase II clinical studies; higher manufacturing expenses for VAX31, as we advance that program toward our anticipated IND application submission; and increased personnel-related costs in our R&D organization to support these key initiatives.

研發費用的同比增長主要是由於 VAX-24 的製造和臨床開發費用增加，因為我們投資準備計劃中的 III 期臨床試驗並啟動並完成了 2 項 II 期臨床研究的入組； VAX31的製造費用更高，因為我們將該計劃推進到我們預期的 IND 申請提交；並增加了我們研發組織的人員相關成本，以支持這些關鍵舉措。

The increase in G&A expenses was driven principally by higher personnel-related and corporate costs as we invested in our team and infrastructure to support our overall growth. I will note the $23 million charge we incurred in the fourth quarter related to the agreement we entered into with Sutro Biopharma during that period. This amount reflects the upfront cash and stock consideration for the expanded rights we acquired and the option we have to acquire additional rights. The entire upfront consideration was expensed in the fourth quarter.

G&A 費用的增加主要是由於我們投資於我們的團隊和基礎設施以支持我們的整體增長而導致的人員相關成本和公司成本增加。我會注意到我們在第四季度產生的 2300 萬美元費用與我們在此期間與 Sutro Biopharma 簽訂的協議有關。這一數額反映了我們獲得的擴大權利的前期現金和股票對價以及我們必須獲得額外權利的選擇權。整個前期對價已在第四季度支出。

As we look forward, we expect a substantial increase in 2023 expenses over full year and Q4 2022 annualized levels, excluding the $23 million Sutro charge, particularly in R&D. The expected significant increase in R&D expenses is primarily a function of our investment to make the required clinical trial materials for our planned VAX-24 Phase III program, which will consist of multiple trials and, to a much lesser degree, expenses related to executing our VAX-24 infant Phase II study, preparing for our planned VAX-31 adult Phase I/II study, activities to support a future BLA for VAX-24 and an increase in employee head count to support our anticipated growth.

展望未來，我們預計 2023 年的支出將比全年和 2022 年第四季度的年化水平大幅增加，不包括 2300 萬美元的 Sutro 費用，特別是在研發方面。研發費用的預期顯著增加主要是我們投資為我們計劃的 VAX-24 III 期項目製作所需臨床試驗材料的函數，該項目將包括多項試驗，並且在較小程度上與執行我們的相關費用有關VAX-24 嬰兒 II 期研究，為我們計劃的 VAX-31成人 I / II 期研究做準備，支持 VAX-24 未來 BLA 的活動以及增加員工人數以支持我們的預期增長。

Turning to the balance sheet and cash runway. As Grant noted, we continued to maintain a strong financial position, ending 2022 with $957.9 million in cash, cash equivalents and investments. Going forward, we expect that our balance sheet will be sufficient to fund our operating expenses and capital expenditure requirements through a number of important milestones over the next few years, including the top line pivotal VAX-24 Phase III noninferiority study in adults, for which data is expected in 2025.

轉向資產負債表和現金跑道。正如格蘭特指出的那樣，我們繼續保持強勁的財務狀況，到 2022 年底，我們擁有 9.579 億美元的現金、現金等價物和投資。展望未來，我們預計我們的資產負債表將足以通過未來幾年的許多重要里程碑為我們的運營費用和資本支出需求提供資金，包括成人的重要 VAX-24 III 期非劣效性研究，為此數據預計在 2025 年。

As we've noted before, our cash runway outlook does not reflect the potential costs associated with securing additional manufacturing capacity to support for certain components of our vaccine, expected increased commercial quantities upon the potential approval and launch of VAX-24 in the infant population and to expand into other markets outside of the United States. We continue to evaluate our alternatives to bring on such additional capacity.

正如我們之前所指出的，我們的現金跑道前景並未反映與確保額外製造能力以支持我們疫苗的某些成分相關的潛在成本，以及在可能批准和在嬰兒人群中推出 VAX-24 後預期增加的商業數量並擴展到美國以外的其他市場。我們將繼續評估我們的替代方案以帶來這種額外的能力。

I will now turn it over to Grant for closing remarks.

我現在將把它轉交給格蘭特作結束語。

Thanks, Andrew. It was an extraordinary year of validation for VAX-24 in our pipeline, and we are in a position to maintain our strong momentum in 2023. We expect this to be a milestone-rich year across our pipeline with a focus on VAX-24 and VAX-31. We look forward to sharing further updates as the year progresses and appreciate your interest by joining us today.

謝謝，安德魯。這是對我們管道中的 VAX-24 進行驗證的不平凡的一年，我們能夠在 2023 年保持強勁勢頭。我們預計今年將是我們整個管道中具有里程碑意義的一年，重點是 VAX-24 和VAX-31。隨著時間的推移，我們期待分享更多更新，感謝您今天加入我們的興趣。

With that, let's take some questions. Operator?

有了這個，讓我們提出一些問題。操作員？

(Operator Instructions) Our first question will be coming from Jason Gerberry of Bank of America.

（操作員說明）我們的第一個問題將來自美國銀行的 Jason Gerberry。

My first question is just as you move back to '24 into peds, just your thoughts on the biggest risk, the translatability of vaccine efficacy, going to the pediatric population with a higher valency product. And then my second question, just wanted to get your thoughts regarding the recent ACIP panel and discussion on Pfizer's PCV20 in peds. And if the FDA ultimately agrees with Pfizer's view on totality of data and coverage at the fourth dose, might that in any way alter how you're thinking about pediatric development of VAX-24?

我的第一個問題是，當你回到 24 歲時，你對最大風險的想法，即疫苗功效的可轉化性，以及更高效價產品對兒科人群的影響。然後是我的第二個問題，只是想了解您對最近的 ACIP 專家組和輝瑞 PCV20 在 peds 中的討論的看法。如果 FDA 最終同意輝瑞公司關於第四劑數據和覆蓋範圍的整體觀點，這是否會以任何方式改變您對 VAX-24 兒科開發的看法？

Jason, thanks for the question. There's been a long history of PCV development initially beginning in peds and then graduating to adults and then more recently, starting in adults and then going into peds. And there's been remarkable consistency using the same formulation whether it was Prevnar or Merck's version, VAXNEUVANCE, where they were able to take the exact same dose and same formulation in both infants and adults. Obviously, a different number of doses more being administered to kids. But there's been very good translatability across the age groups historically.

傑森，謝謝你的提問。 PCV 的發展有著悠久的歷史，最初是從兒童開始，然後逐漸發展到成人，然後最近，從成人開始，然後進入兒童。無論是 Prevnar 還是 Merck 的版本 VAXNEUVANCE，使用相同的配方都具有顯著的一致性，他們能夠在嬰兒和成人中服用完全相同的劑量和相同的配方。顯然，不同數量的劑量更多地施用於兒童。但從歷史上看，跨年齡組的可譯性非常好。

But I think what we have seen, shown consistently is bigger drop as expanded valence PCVs had gone from adults down to kids. And as you referenced, that was the subject of the discussion at last week's ACIP meeting, where the conclusion of the working group was, on the one hand, we have the improved coverage of PCV20. But on the other hand, you have higher immune responses with the 15-valent for Merck.

但我認為我們所看到的、持續顯示的是更大的下降，因為擴展的化合價 PCV 從成人到兒童。正如你提到的，這是上週 ACIP 會議上討論的主題，工作組的結論是，一方面，我們提高了 PCV20 的覆蓋率。但另一方面，默克的 15 價免疫反應更高。

So that's the trade-off that's being required with the conventional technology, and that's what has us so excited about the data that we generated last fall, where VAX-24 was able to show broader coverage, but in fact, better immune responses against the common strains of the less valent vaccine. So that's the existential choice that they're being forced to make. And the working group basically didn't really indicate how they are going to act, but that's the trade-off that they're going to have to consider if the April PDUFA date comes and the FDA approves Prevnar 20.

所以這就是傳統技術所需要的權衡，這就是我們對去年秋天生成的數據感到如此興奮的原因，其中 VAX-24 能夠顯示更廣泛的覆蓋範圍，但實際上，針對低價疫苗的常見毒株。所以這是他們被迫做出的生存選擇。工作組基本上沒有真正表明他們將如何行動，但如果 PDUFA 的 4 月日期到來並且 FDA 批准 Prevnar 20，他們將不得不考慮權衡取捨。

Our next question is coming from Roger Song of Jefferies.

我們的下一個問題來自 Jefferies 的 Roger Song。

Maybe just a quick 2 question related to the statistics. So for the upcoming (inaudible) Phase II data readouts, understanding you want to focus on the point estimate given the smaller size, but maybe can help us to contextualize what is the level of point estimate you need to hit in order to have a reasonable chance in the Phase III to hit a noninferiority? That's number one.

也許只是一個與統計相關的快速 2 問題。因此，對於即將到來的（聽不清）第二階段數據讀數，了解您想要關注較小尺寸的點估計，但也許可以幫助我們將您需要達到的點估計水平背景化，以便獲得合理的在第三階段有機會打出非劣勢？這是第一。

Number two is, in terms of the sample size for Phase III, since you are targeting around 1,000 patients, how should we think about with different data scenario in terms of the noninferior versus the superior for some serotypes?

第二，就 III 期的樣本量而言，由於您的目標是大約 1,000 名患者，我們應該如何根據某些血清型的非劣效與優效來考慮不同的數據場景？

Roger, thanks for the question. Yes, as Jim was touching on in the prepared remarks, what we've seen consistently in the historical Phase III studies for the adult space is that you can have as low as a 0.6 point estimate on a relative basis for your vaccine versus the standard of care, which would be Prevnar 20. And that has been about the minimum amount you need to show to make room for the point -- for the confidence intervals on either side.

羅傑，謝謝你的提問。是的，正如吉姆在準備好的發言中提到的那樣，我們在成人空間的歷史 III 期研究中一貫看到的是，相對於你的疫苗與標準的相對基礎，你可以得到低至 0.6 點的估計小心，這將是 Prevnar 20。這大約是您需要顯示的最小數量，以便為該點騰出空間 - 為兩側的置信區間。

So yes, as we're approaching that 65-plus readout, those are the sort of point estimates we'll be looking to exceed. And as we saw from the larger study that we read out in the fall, we are well in excess of those. So we're feeling reassured as we did the prespecified stratification, and we're able to look at the 60- and 64-year-old age cohort. So yes, I think we feel like we're tracking.

所以是的，當我們接近 65+ 讀數時，這些是我們希望超過的那種點估計。正如我們在秋季讀出的更大規模的研究中看到的那樣，我們遠遠超過了那些。因此，我們在進行預先指定的分層時感到放心，並且我們能夠查看 60 歲和 64 歲的年齡組。所以是的，我認為我們感覺我們正在追踪。

And then last week, the pediatric data for PCV20 was released. And once again, we saw that they could go down as low as 0.6, which they were at for a few strains. I know one in particular, they got 0.6 in the number that were closed. And again, that was adequate to exceed the noninferiority threshold. So I think we're seeing that sort of consistency across adults and pediatrics that has been a bit of a hallmark in this space.

然後在上週發布了 PCV20 的兒科數據。再一次，我們看到它們可能會低至 0.6，它們在幾個菌株中都處於這個水平。我特別知道一個，他們關閉的數量為 0.6。同樣，這足以超過非劣效性閾值。所以我認為我們正在看到成人和兒科之間的這種一致性，這已經成為這個領域的一個標誌。

And then, Jim, why don't you take the second part about superiority?

然後，吉姆，你為什麼不參加關於優越感的第二部分？

Sure. I think that what you're seeing with our data from the 50 to 64 is that's reproducible in the 65-plus. We feel comfortable with the Phase III side that we can repeat the statistical superiority for the 4 that we had seen in the 50 to 64. But we could, in fact, if we, again, repeat what we've seen in the 50 to 64 in the Phase III goes to as high as 8 or 9, depending upon what the FDA says, would be the requirement for the lower bound to demonstrate superiority. If it's a lower bound of 1.0 or greater, we think that we can hit 7 or 8 of those.

當然。我認為你從我們 50 歲到 64 歲的數據中看到的是在 65 歲以上的人中可以重現的。我們對第三階段感到滿意，因為我們可以重複我們在 50 到 64 期間看到的 4 的統計優勢。但事實上，如果我們再次重複我們在 50 到 64 期間看到的情況，我們可以III 期的 64 達到 8 或 9，這取決於 FDA 的說法，這將是證明優勢的下限要求。如果它的下限為 1.0 或更高，我們認為我們可以達到其中的 7 或 8 個。

Our next question will be coming from David Risinger of SVB.

我們的下一個問題將來自 SVB 的 David Risinger。

Thank you for the updates. So I have 2 questions. First, obviously, you're planning Phase II in infants with VAXNEUVANCE as the comparator. But assuming Prevnar 20 is approved in infants in April, and it's given an equal recommendation to VAXNEUVANCE by the ACIP this summer, should we just assume that down the line in a couple of years, you would ultimately run a Phase III in infants versus Prevnar 20?

感謝您的更新。所以我有兩個問題。首先，很明顯，您計劃以 VAXNEUVANCE 作為比較對像在嬰兒中進行 II 期試驗。但假設 Prevnar 20 在 4 月份獲得批准用於嬰兒，並且今年夏天 ACIP 向 VAXNEUVANCE 提供了同等的推薦，我們是否應該假設幾年後，您最終將在嬰兒和 Prevnar 中進行 III 期試驗20？

And then second, just to follow up on Jim's comment a moment ago, why would the lower bound be different for your Phase III in adults? I think you had said if the lower bound was 1.0 or greater, you might be able to hit 7 to 8 of those or something. I just wanted to understand that a little bit better.

其次，只是跟進 Jim 剛才的評論，為什麼成人 III 期的下限會有所不同？我想你曾說過，如果下限是 1.0 或更高，你可能能夠達到其中的 7 到 8 個。我只是想更好地理解這一點。

David, thank you for the question. Yes, so the ACIP conversation last week would suggest that PCV20 is on a path toward approval. We'll find out soon enough when the FDA decides in April. But looking forward to our own Phase II clinical study that we've already guided to beginning in the second quarter of this year, we have 2 different stages for that study. The first stage is a safety look, for which we have been planning to compare to PCV15. And as you say, if they give a joint recommendation, starting out against PCV15 will be more than adequate.

大衛，謝謝你的提問。是的，所以上週的 ACIP 對話表明 PCV20 正在走向批准。當 FDA 在四月份做出決定時，我們很快就會知道。但是期待我們已經指導在今年第二季度開始的我們自己的 II 期臨床研究，我們有兩個不同的階段進行該研究。第一階段是安全外觀，為此我們一直計劃與 PCV15 進行比較。正如您所說，如果他們給出聯合建議，那麼從對抗 PCV15 開始就綽綽有餘了。

But to your point, there is a precedent where the agency has asked to compare to the broadest spectrum standard-of-care vaccine that's out there. So we will be making preparations in order to potentially switch from PCV15 to PCV20 for that Stage II portion of that study, and that would be a chord we strike with each of the investigators who'd be participating in the study. But given the interactions that we've had with the FDA, although we could theoretically have the alternative, I think the preference would be that the FDA would want us to compare to the broadest spectrum one, and we'll do it -- we'll be doing what we can to potentially alter that original plan, but that will be a bit of a work in progress as things unfold with the FDA and then ACIP.

但就你的觀點而言，有一個先例，即該機構要求與現有的最廣譜護理標準疫苗進行比較。因此，我們將做好準備，以便在該研究的第二階段部分從 PCV15 轉換為 PCV20，這將引起我們對參與該研究的每位研究人員的共鳴。但考慮到我們與 FDA 的互動，雖然理論上我們可以有替代方案，但我認為首選是 FDA 希望我們與最廣譜的比較，我們會這樣做 - 我們我們將盡我們所能來改變最初的計劃，但隨著 FDA 和 ACIP 的進展，這將是一項正在進行的工作。

And then you had a second question with regard to the lower bound. I hope that wasn't something that I confused the issue around. The technical lower bound threshold in order to show the noninferiority standard is still to exceed 0.5, but that's where the lower limit of the 95th confidence interval needs to exceed. And what we were saying was the point estimate, if it's at 0.6, that's usually enough for that lower limit to exceed 0.5.

然後你有關於下限的第二個問題。我希望這不是我混淆問題的原因。顯示非劣效性標準的技術下界閾值仍然要超過0.5，但這是第95個置信區間的下限需要超過的地方。我們所說的是點估計，如果它是 0.6，通常下限超過 0.5 就足夠了。

But was that more related to the superiority? Okay, Jim, why don't you take it from there?

但這與優勢更相關嗎？好吧，吉姆，你為什麼不從那裡拿走它呢？

Yes. So for the superiority, what I've seen in the past year is that sometimes, the FDA wants to take into account some assay variability because if they're going to put a statistical superiority claim in your label, they want to make sure that you're absolutely sure that it's superior. So it wouldn't be materially higher than 1.0, but it might be slightly higher to give some degree of leeway in case there's some massive variability. So we don't expect it not to be 1.0, but even if it's even higher, I think we can achieve at least 4 and more.

是的。因此，對於優勢，我在過去一年中看到的是，有時，FDA 想要考慮一些化驗變異性，因為如果他們要在您的標籤中提出統計優勢聲明，他們想要確保你絕對確定它是優越的。所以它不會實質性地高於 1.0，但它可能會略高一些，以提供一定程度的迴旋餘地，以防出現一些巨大的可變性。所以我們不期望它不是1.0，但即使再高，我覺得我們至少可以做到4以上。

And then the last thing I'll say on that is that even if we aren't able to get superiority claim in the label, that absolute immunogenicity value will then reset the bar for others to demonstrate noninferiority again. So even if it's not on the label, we'll have raised the bar for others who want to follow to demonstrate noninferiority.

然後我要說的最後一件事是，即使我們無法在標籤中獲得優勢聲明，絕對免疫原性值也會重新設置其他人再次證明非劣效性的標準。因此，即使它不在標籤上，我們也會提高其他想要遵循以證明非劣效性的標準。

Our next question will be coming from Seamus Fernandez of Guggenheim.

我們的下一個問題將來自古根海姆的 Seamus Fernandez。

So really wanted to drill in a little bit to VAX-31. Just hoping you guys could provide us with a little bit of color on what it's going to take to get that IND through, expand the manufacturing to the 31-valent targets?

所以真的很想深入了解 VAX-31。只是希望你們能為我們提供一些關於如何通過 IND，將製造擴展到 31 價目標的顏色？

And then separately, I was just hoping you might help us understand where you see the real differentiation opportunity for VAX-31. My impression was that the team was really thinking about some unique opportunities, particularly in otitis media as an opportunity there. So just love to touch on VAX-31.

然後分別地，我只是希望你能幫助我們了解你在哪裡看到 VAX-31 的真正差異化機會。我的印像是，該團隊確實在考慮一些獨特的機會，尤其是在中耳炎領域。所以只是喜歡觸摸 VAX-31。

Yes. Thanks for the question, Seamus. So as it relates to the VAX-31 program, we've guided to an IND going into the second half of this year. And like we saw with VAX-24 last year, these adult studies accrue and read out quickly. So we have guided to being in receipt of the data from that study, top line data next year in 2024.

是的。謝謝你的問題，Seamus。因此，由於它與 VAX-31 計劃相關，我們已指導 IND 進入今年下半年。就像我們去年在 VAX-24 上看到的那樣，這些成人研究的積累和讀出速度很快。因此，我們已指導接收該研究的數據，即明年 2024 年的頂級數據。

So in order for us to be able to guide to an IND in the second half, it means we're well on our way from a manufacturing perspective. We've said publicly that we made a surplus of the 24 drug substances that are in both VAX-24 and VAX-XP. So what we've been in the process of doing is manufacturing the incremental 7 polysaccharides and then conjugates and then doing the drug product formulation work.

因此，為了讓我們能夠在下半年引導 IND，這意味著我們從製造的角度來看進展順利。我們已經公開表示，我們生產了 VAX-24 和 VAX-XP 中的 24 種藥物。所以我們一直在做的是製造增量的 7 種多醣，然後結合，然後進行藥物產品配方工作。

So what we've said in other conversations is that we're well on our way. We've made all the polysaccharides under GMP. We've made the conjugates and now we're heading towards the drug product formulation stage. And so far, so good. And as per today, we're maintaining that guidance of second half IND filing. So really excited about that, and we believe we'll be able to leverage the same Lonza infrastructure for the production of VAX-31 that we've been budgeting for, for VAX-24.

因此，我們在其他對話中所說的是，我們進展順利。我們已經在 GMP 下製造了所有的多醣。我們已經製造了偶聯物，現在我們正朝著藥品配方階段邁進。到目前為止，一切都很好。根據今天，我們將維持下半年 IND 申請的指導。對此真的很興奮，我們相信我們將能夠利用相同的 Lonza 基礎設施來生產我們一直在為 VAX-24 制定預算的 VAX-31。

As it relates to the differentiation, maybe Jim and I can tag-team this one. But for starters, in the adult space, once you get up to 31 strains, you're effectively covering the evidenced pathogenic serotypes for pneumococci. So in the U.S., those 31 conjugates will cover 95% of the circulating disease. In Europe, it gets as high as 98%.

由於它涉及到差異化，也許吉姆和我可以標記團隊這個。但對於初學者來說，在成人領域，一旦菌株達到 31 種，就可以有效地涵蓋已證實的肺炎球菌致病血清型。因此在美國，這 31 種結合物將覆蓋 95% 的循環疾病。在歐洲，這一比例高達 98%。

So you really feel like you covered the gamut once you get to these 31 conjugates. And what we think we can do with the carrier-sparing technology that we possess is not only scale to cover those newly circulating strains, but not take the pressure off those strains that have historically been pathogenic but have been brought under control with vaccination currently.

因此，一旦接觸到這 31 種偶聯物，您真的會覺得自己涵蓋了整個色域。我們認為我們可以利用我們擁有的攜帶者備用技術做的不僅是擴大規模以覆蓋那些新傳播的菌株，而且不會減輕那些歷史上具有致病性但目前已通過疫苗接種得到控制的菌株的壓力。

And so this is the big opportunity that we have, and we don't believe we face the same trade-off that the conventional PCV developers are facing where to get the kind of coverage of the newly circulating strains, they have to no longer include those strains that have been taken out of circulation. So as we mentioned in the prepared remarks, there's historical precedent where vaccination has been withdrawn for currently covered -- controlled strain can result in a rebound.

因此，這是我們擁有的巨大機會，我們認為我們不會面臨與傳統 PCV 開發人員所面臨的相同的權衡取捨，從哪裡獲得新傳播菌株的覆蓋範圍，他們必須不再包括那些已經退出流通的毒株。因此，正如我們在準備好的評論中提到的那樣，有一個歷史先例，即針對當前覆蓋的疫苗接種已被取消——受控菌株可能導致反彈。

So it's more than just the coverage advantage. It's also the maintenance of the no longer circulating strains. So that is a big opportunity for us in the adult space. And then your reference to the otitis media is another aspect of the potential advantage as it relates to the infant indication.

因此，這不僅僅是覆蓋範圍的優勢。這也是不再流行的菌株的維持。所以這對我們在成人領域來說是一個巨大的機會。然後你提到中耳炎是潛在優勢的另一個方面，因為它與嬰兒適應症有關。

So Jim, maybe you can talk a little bit about that?

吉姆，也許你可以談談這個？

Yes. And I'd say first in the infant, VAX-31 will increase coverage against IPD by about 25% or more from what would be the standard of care if PCV20 makes it through the PDUFA date. Even more so, if it's referenced against PCV15. So there is still a substantial impact on invasive disease.

是的。我要說的是，首先在嬰兒中，如果 PCV20 在 PDUFA 日期之前通過，VAX-31 將使針對 IPD 的覆蓋率比護理標準增加約 25% 或更多。更重要的是，如果它是針對 PCV15 的引用。因此對侵襲性疾病仍有實質性影響。

But in terms of otitis media, especially 35B serotype, there's a lot more contribution to otitis media in these incremental strains that are in VAX-31, and you get 48% increase in coverage of otitis media. And when you think about it, the incident rate is almost to the point where every kid gets at least 1 ear infection. So -- and if about 35%, 40% of those are of Strep pneumoniae, you can see that that's a ubiquitous disease.

但就中耳炎而言，尤其是 35B 血清型，VAX-31 中的這些增量菌株對中耳炎的貢獻更大，中耳炎的覆蓋率增加了 48%。仔細想想，事故率幾乎達到每個孩子至少感染 1 次耳部的程度。所以——如果其中約 35%、40% 是肺炎鏈球菌，你就會發現這是一種普遍存在的疾病。

So this incremental 48% could have a substantial impact, obviously, on medical expenses, but also on antimicrobial resistance because it's one of the main drivers for antibiotic scripts in this young age group as well. So that's why we're excited about this for otitis media.

因此，這一增加的 48% 顯然會對醫療費用產生重大影響，但也會對抗菌素耐藥性產生重大影響，因為它也是這個年輕年齡組抗生素處方的主要驅動因素之一。這就是為什麼我們對中耳炎感到興奮。

The next question is coming from Yoon Choi of Evercore.

下一個問題來自 Evercore 的 Yoon Choi。

This is actually Jon Miller on Evercore. But I'd love to ask about manufacturing expansion that you're talking about. Obviously, this is -- you've talked about only being able to currently do the U.S. But what would it take to do a much larger manufacturing footprint? Is this something that you could do in-house? Would this be a larger Lonza deal? And maybe if you could put some bookends on how much a full-size manufacturing footprint might cost in various scenarios.

這實際上是 Evercore 上的 Jon Miller。但我想問一下你正在談論的製造業擴張。顯然，這是——你談到目前只能在美國做，但要做更大的製造足跡需要什麼？這是你可以在內部做的事情嗎？這會是一筆更大的龍沙交易嗎？也許如果你能把一些書擋放在不同情況下全尺寸製造足跡可能花費多少的書擋上。

Jon, thank you for the question. We'll tag-team this one as well. I'll have Andrew bring it home. But just in terms of order of magnitude, I think the way people should be thinking about that U.S. adult launch-related capacity in the tens of millions of doses. Whereas when you ultimately get into the full-fledged adult and infant and sort of global reach capacity, PCV demand does get into the greater than 100 million doses per year sort of territory. So we're talking about that sort of line of demarcation.

喬恩，謝謝你的提問。我們也將標記團隊這個。我會讓安德魯把它帶回家。但就數量級而言，我認為人們應該以數千萬劑的方式思考美國成人與發射相關的能力。而當你最終進入成熟的成人和嬰兒以及某種全球覆蓋能力時，PCV 需求確實進入了每年超過 1 億劑的領域。所以我們談論的是那種分界線。

And then as it relates to the second part of that question, I'm not quite sure how far Andrew will be able to go. But I'll hand it to Andrew.

然後，由於涉及到該問題的第二部分，我不太確定安德魯能走多遠。但我會把它交給安德魯。

Yes, Jon, again, thanks for the question. We are looking at different options in terms of strategy that includes doing it on our own facility, using Lonza with whom we have a great and long-standing partnership and other CDMO options as well. And obviously, the magnitude, it will depend on the route we take.

是的，喬恩，再次感謝你提出這個問題。我們正在考慮戰略方面的不同選擇，包括在我們自己的設施上進行，使用與我們有良好和長期合作夥伴關係的龍沙，以及其他 CDMO 選項。顯然，幅度將取決於我們採取的路線。

And when we pull the trigger, that's something over the next 12 to 18 months, we're likely to do, so we can ensure we have the necessary capacity to meet the demand, subsequent -- few years subsequent to the launch. Probably premature at this time to kind of range the options, but we're hoping to be in a position to do that in the not-too-distant future as we get further down the valuation.

當我們扣動扳機時，那是在接下來的 12 到 18 個月內，我們很可能會這樣做，因此我們可以確保我們有必要的能力來滿足需求，隨後 - 推出後幾年。目前可能還為時過早，但隨著我們進一步降低估值，我們希望在不久的將來能夠做到這一點。

Okay. That makes sense. Is this a sort of thing that you expect Lonza would have the capacity to do already if you ask them tomorrow to do it?

好的。這就說得通了。如果您明天要求 Lonza 做這件事，您是否希望他們已經有能力做這種事情？

Well, we can -- as Grant noted, we can satisfy the expected demand in the adult population in the U.S. out of the existing facilities. As to whether Lonza today starts one of the evaluations, it's likely. They have basically built custom dedicated space for their clients. So it's likely we would need to work and partner with them to develop, build that capacity. So that's something that we're looking into, but it would likely be an undertaking.

好吧，我們可以——正如格蘭特指出的那樣，我們可以利用現有設施滿足美國成年人口的預期需求。至於龍沙今天是否開始其中一項評估，很有可能。他們基本上已經為他們的客戶建立了定制的專用空間。因此，我們很可能需要與他們合作並與他們合作，以發展和建立這種能力。所以這是我們正在研究的事情，但這可能是一項承諾。

The next question is coming from Louise Chen of Cantor.

下一個問題來自 Cantor 的 Louise Chen。

Congratulations on the quarter. So one question we often get is since that you've already shared proof-of-concept for VAX-24, and because the market for PCVs is getting crowded, why not just move forward with VAX-31?

祝賀這個季度。所以我們經常遇到的一個問題是，既然您已經分享了 VAX-24 的概念驗證，並且由於 PCV 市場越來越擁擠，為什麼不繼續推進 VAX-31？

And then second question I had for you was on the market opportunities for VAX-A1, PG and GI, what do you think of those? How do you think about potential peak sales versus what you might see for your PCV? And when do you plan to start studying for these opportunities? Will it be within the next several years or after you kind of move through the pivotal stuff with your PCV?

然後我要問你的第二個問題是關於 VAX-A1、PG 和 GI 的市場機會，你如何看待這些？您如何看待潛在的銷售高峰期與您可能看到的 PCV？你打算什麼時候開始學習這些機會？是在接下來的幾年內，還是在您通過 PCV 完成關鍵任務之後？

Thanks for the question, Louise. Yes, I mean certainly, VAX-31 is going to be -- I mean I'm on record for calling it a category killer. But the reality is VAX-24 has a best-in-class profile in both the adult and infant market, and it is on the fastest track to introduction to the market. And so it's our primary focus to deliver that vaccine to the market. We believe that VAX-24 is going to be a tremendous introduction for our carrier-sparing PCVs to the market.

謝謝你的問題，路易絲。是的，我的意思是肯定的是，VAX-31 將會——我的意思是我將其稱為類別殺手。但現實情況是，VAX-24 在成人和嬰兒市場上都擁有一流的形象，並且正以最快的速度推向市場。因此，將疫苗推向市場是我們的首要任務。我們相信，VAX-24 將成為我們的運營商備用 PCV 推向市場的重要舉措。

And we know that upon widespread use of VAX-24, it's only going to enhance the rate of circulating disease for these strains over and above those that are in VAX-24. So we know VAX-31 is going to be important. And we have it moving as fast as it can. And with what we know today, this is the right strategy for the company. If there was something to change either from a competitive dynamic perspective or from an epidemiology perspective, we would be in a position to revisit that, but we believe this is the right way to maximize value for Vaxcyte. And we think it's the right thing to do societally as a global health solution.

我們知道，在廣泛使用 VAX-24 後，它只會提高這些菌株的循環疾病發生率，超過 VAX-24 中的那些。所以我們知道 VAX-31 將很重要。我們讓它盡可能快地移動。就我們今天所知，這對公司來說是正確的戰略。如果從競爭動態的角度或流行病學的角度來看有什麼需要改變的，我們將能夠重新審視它，但我們相信這是使 Vaxcyte 價值最大化的正確方法。我們認為將社會作為全球健康解決方案是正確的做法。

And then as it relates to the pipeline, yes, we think that what we can do with this cell-free protein synthesis platform is going to continue to pay dividends. VAX-A1 is our broad spectrum Group A Strep vaccine. We've all been hearing about increasing rates of the circulation of Group A Strep infections. And like PCVs, Group A Strep afflicts adults and infants.

然後因為它與管道有關，是的，我們認為我們可以用這個無細胞蛋白質合成平台做的事情將繼續帶來紅利。 VAX-A1 是我們的廣譜 A 組鏈球菌疫苗。我們都聽說過 A 組鏈球菌感染的傳播率增加。和 PCV 一樣，A 組鏈球菌感染成人和嬰兒。

So this is an important and what could be valuable intervention on both ends of the age spectrum. So we're moving that program forward aggressively. And because of that widespread usage, we do think it has blockbuster potential given the magnitude of morbidity and mortality that it can address.

因此，這是一項重要且可能對年齡段兩端有價值的干預措施。因此，我們正在積極推進該計劃。由於廣泛使用，鑑於它可以解決的發病率和死亡率的嚴重程度，我們確實認為它具有重磅炸彈的潛力。

And then as it relates to the other programs, VAX-PG, we've nominated the lead candidate that we want to advance to address this therapeutic solution for periodontitis. Likewise, we are very excited about the new VAX-GI program for shigellosis.

然後，由於它與其他項目 VAX-PG 相關，我們已經提名了我們想要推進的主要候選人，以解決牙周炎的治療解決方案。同樣，我們對針對志賀氏菌病的新 VAX-GI 計劃感到非常興奮。

Just on Friday, the CDC came out with an alert about an alarming rate of antibiotic resistance associated with shigella. So we're moving them forward as fast as we can, but in sync with the value equation with PCV at the lead. But we certainly expect to bring on additional programs coming out of our pipeline going forward.

就在周五，疾病預防控制中心發出警報，稱與志賀氏菌相關的抗生素耐藥性達到了驚人的速度。因此，我們正在盡可能快地推動它們向前發展，但與 PCV 領先的價值方程同步。但我們當然希望在未來推出更多計劃。

Our next question is coming from Joseph Stringer of Needham.

我們的下一個問題來自李約瑟的約瑟夫斯金格。

Just given that there's a competitor, 24-valent pneumococcal vaccine program out there in mid-stage development, can you explain the relative importance of potentially being first to market? And do you think that your current time lines for VAX-24 Phase III data readouts put you in a good position relative to that 24-valent competitor?

鑑於有一個競爭對手 24 價肺炎球菌疫苗項目處於中期開發階段，您能解釋一下可能率先上市的相對重要性嗎？您是否認為您當前的 VAX-24 III 期數據讀出時間線使您相對於那個 24 價競爭對手處於有利位置？

Yes. Thanks for the question, Joey. Indeed, there is another 24-valent vaccine that has reported Phase II data in adults. It's the program that GSK is administering to in this moment. The difference is it's -- the defining aspect of pneumococcal conjugate vaccines is the covalent bond between the polysaccharide sugar and the protein. And that's been critically important because it ensures that both the sugar and the protein are co-presented to the immune system simultaneously. And non-covalent approaches haven't been able to assure that.

是的。謝謝你的問題，喬伊。事實上，還有另一種 24 價疫苗已經報告了成人的 II 期數據。這是葛蘭素史克目前正在管理的項目。不同之處在於——肺炎球菌結合疫苗的決定性方面是多醣糖和蛋白質之間的共價鍵。這一點非常重要，因為它確保糖和蛋白質同時共同呈現給免疫系統。非共價方法無法確保這一點。

So this is a non-covalent-bound approach that they're moving forward. And what they've said in their own public filings is that they don't expect to be able to launch that program until the back end of this decade. So it does put VAX-24 in a position to find its way to the market potentially significantly earlier than that particular program.

所以這是他們正在推進的一種非共價結合的方法。他們在自己的公開文件中表示，他們預計要到本世紀末才能啟動該計劃。因此，它確實使 VAX-24 能夠比該特定程序更早地找到進入市場的途徑。

And as it relates to first-mover advantages, usually that's valuable unless the second or third to market have a material advantage. And when we look objectively about what we're doing and the data we've generated, we feel like we've got the more tried-and-true approach. We think we've got an extremely compelling immunogenicity data and a safety profile that looks remarkably similar to the already approved pneumococcal conjugate vaccines.

由於它涉及先發優勢，通常這是有價值的，除非第二或第三進入市場的人具有物質優勢。當我們客觀地看待我們正在做的事情和我們生成的數據時，我們覺得我們已經有了更可靠的方法。我們認為我們已經獲得了極其令人信服的免疫原性數據和看起來與已經批准的肺炎球菌結合疫苗非常相似的安全性概況。

And the hallmark of these covalent-bound PCVs is the ability to boost because that protein carrier and its T-cell epitopes being presented to the immune system simultaneously are what deliver that key boost effect. And that's what is often lost when it's not presented simultaneously is that ability to deliver a boost.

這些共價結合的 PCV 的標誌是增強能力，因為同時呈現給免疫系統的蛋白質載體及其 T 細胞表位是提供關鍵增強作用的因素。當它沒有同時呈現時，經常會丟失的是提供提升的能力。

And certainly, in the infant market, that's the price of admission you have to be able to boost in a material way, and we think the adult market is going in that direction also. So we're always vigilant about the competition. But we think we're in an extremely enviable position in this moment as it relates to that particular program.

當然，在嬰兒市場，這是你必須能夠以物質方式提高的入場費，我們認為成人市場也在朝著這個方向發展。所以我們總是對競爭保持警惕。但是我們認為我們在這一刻處於一個非常令人羨慕的位置，因為它與那個特定的程序有關。

Thank you. This concludes today's conference call. You may all disconnect. Everyone, have a great day.

謝謝。今天的電話會議到此結束。你們都可以斷開連接。大家，祝你有美好的一天。

Thanks, everybody.

謝謝大家。