Attenuated live varicella virus vaccine(Merck)

RAHWAY, N.J.--( BUSINESS WIRE )--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced financial results for the fourth quarter and full year of 2023. “ 2023 was another very strong year for Merck. I am extremely pleased by the progress we’ve made to develop and deliver transformative therapies and vaccines that will help save and improve lives around the world. We reached more than 500 million people with our medicines last year alone, over half of which were donations, including through our program to treat river blindness,” said Robert M. Davis, chairman and chief executive officer, Merck. “ We also made investments of approximately $30 billion in research and development in our ongoing effort to discover, develop and collaborate to propel the next generation of impactful innovations. As we move forward, I’m confident that our strong momentum will continue, underpinned by the unwavering dedication of our talented global team.” Financial Summary $ in millions, except EPS amounts Fourth Quarter Year Ended 2023 2022 Change Change Ex-Exchange Dec. 31, 2023 Dec. 31, 2022 Change Change Ex-Exchange Sales $14,630 $13,830 6% 7% $60,115 $59,283 1% 4% GAAP net (loss) income 1 (1,226) 3,017 N/M N/M 365 14,519 -97% -95% Non-GAAP net income that excludes certain items 1,2* 66 4,129 -98% N/M 3,837 19,005 -80% -75% GAAP EPS (0.48) 1.18 N/M N/M 0.14 5.71 -98% -95% Non-GAAP EPS that excludes certain items 2* 0.03 1.62 -98% N/M 1.51 7.48 -80% -75% *Refer to table on page 9. N/M - Not meaningful Generally Accepted Accounting Principles (GAAP) loss/earnings per share (EPS) assuming dilution was a loss per share of $0.48 for the fourth quarter and EPS of $0.14 for the full year of 2023. Non-GAAP EPS was $0.03 for the fourth quarter and $1.51 for the full year of 2023. GAAP loss per share and non-GAAP EPS in the fourth quarter of 2023 include a charge of $1.69 per share related to the collaboration with Daiichi Sankyo. GAAP and non-GAAP EPS for the full years of 2023 and 2022 include charges of $6.21 and $0.22 per share, respectively, related to certain collaborations, licensing agreements and asset acquisitions. Non-GAAP EPS excludes acquisition- and divestiture-related costs, including pretax intangible asset impairment research and development (R&D) charges of $779 million in the fourth quarter and full year of 2023 related to gefapixant, and $780 million and $1.7 billion in the fourth quarter and full year of 2022, respectively, primarily related to nemtabrutinib. Non-GAAP EPS also excludes restructuring costs, including costs for the recently approved 2024 Restructuring Program, as well as income and losses from investments in equity securities. Fourth-Quarter Sales Performance The following table reflects sales of the company’s top products and significant performance drivers. Fourth Quarter $ in millions 2023 2022 Change Change Ex-Exchange Commentary Total Sales $14,630 $13,830 6% 7% Pharmaceutical 13,141 12,180 8% 8% Increase driven by growth in oncology, vaccines and hospital acute care, partially offset by a decline in virology, due to LAGEVRIO, and diabetes. Excluding LAGEVRIO and impact of foreign exchange, growth of 14%. KEYTRUDA 6,608 5,450 21% 22% Growth driven by increased global uptake in earlier-stage indications, including triple-negative breast cancer and renal cell carcinoma (RCC), and continued strong global demand from metastatic indications. GARDASIL/GARDASIL 9 1,871 1,470 27% 27% Growth due to strong global demand, particularly in China, and public-sector buying patterns in the U.S. JANUVIA/JANUMET 787 913 -14% -13% Decline primarily due to generic competition in several international markets, particularly in Europe, and lower demand in the U.S. PROQUAD, M-M-R II and VARIVAX 545 526 4% 3% Growth largely due to higher pricing in the U.S. BRIDION 429 441 -3% -3% Decline primarily due to generic competition in certain ex-U.S. markets, particularly in Europe, partially offset by higher demand in the U.S. Lynparza* 315 292 8% 8% Growth driven primarily by higher pricing in the U.S. Lenvima* 226 216 5% 5% Growth primarily due to higher demand in the U.S., partially offset by timing of shipments in China. LAGEVRIO 193 825 -77% -76% Decline due to nonrecurrence of sales in the U.K. and lower demand in Japan and Australia. ROTATEQ 185 139 34% 33% Growth primarily due to public-sector buying patterns in the U.S. and timing of shipments in China. VAXNEUVANCE 176 138 28% 26% Growth largely driven by launches in Europe and continued uptake for the pediatric indication in the U.S. Prior-year quarter benefited from inventory stocking in the U.S. in preparation for pediatric launch. Animal Health 1,278 1,230 4% 4% Growth primarily driven by higher demand for Companion Animal products. Livestock 808 814 -1% 0% Decline primarily due to timing of shipments for ruminant products, largely offset by higher pricing across the product portfolio and higher demand for swine products. Companion Animal 470 416 13% 12% Growth primarily due to higher demand and timing of shipments for BRAVECTO line of products, as well as higher pricing. Sales of BRAVECTO were $197 million and $168 million in the current and prior-year quarters, respectively, which represented growth of 18%, or 19% excluding the impact of foreign exchange. Other Revenues** 211 420 -50% -1% Decline primarily due to impact of revenue hedging activities. *Alliance revenue for this product represents Merck’s share of profits, which are product sales net of cost of sales and commercialization costs. **Other revenues are comprised primarily of revenues from third-party manufacturing arrangements and miscellaneous corporate revenues, including revenue-hedging activities. Full-Year Revenue Performance The following table reflects sales of the company’s top pharmaceutical products, as well as sales of Animal Health products. Year Ended $ in millions Dec. 31, 2023 Dec. 31, 2022 Change Change Ex-Exchange Total Sales $60,115 $59,283 1% 4% Pharmaceutical 53,583 52,005 3% 5% KEYTRUDA 25,011 20,937 19% 21% GARDASIL/GARDASIL 9 8,886 6,897 29% 33% JANUVIA/JANUMET 3,366 4,513 -25% -23% PROQUAD, M-M-R II and VARIVAX 2,368 2,241 6% 6% BRIDION 1,842 1,685 9% 11% LAGEVRIO 1,428 5,684 -75% -74% Lynparza* 1,199 1,116 7% 9% Lenvima* 960 876 10% 11% ROTATEQ 769 783 -2% -1% VAXNEUVANCE 665 170 N/M N/M Animal Health 5,625 5,550 1% 3% Livestock 3,337 3,300 1% 4% Companion Animal 2,288 2,250 2% 3% Other Revenues** 907 1,728 -48% -15% *Alliance revenue for this product represents Merck’s share of profits, which are product sales net of cost of sales and commercialization costs. **Other revenues are comprised primarily of revenues from third-party manufacturing arrangements and miscellaneous corporate revenues, including revenue-hedging activities. N/M - Not meaningful Full-year 2023 pharmaceutical sales grew 3% to $53.6 billion. Pharmaceutical sales growth was primarily driven by higher sales in oncology, particularly KEYTRUDA, higher sales of vaccines, reflecting strong growth of combined sales of GARDASIL/GARDASIL 9 and VAXNEUVANCE, as well as growth in hospital acute care products, including PREVYMIS and BRIDION. Pharmaceutical sales growth in 2023 was partially offset by lower sales of the COVID-19 medication LAGEVRIO, as well as lower sales of JANUVIA and JANUMET, primarily reflecting generic competition in many ex-U.S. markets and lower demand in the U.S., and lower sales of PNEUMOVAX 23 as the market continues to shift toward newer adult pneumococcal conjugate vaccines. Pharmaceutical sales growth for the full year of 2023 was 14% excluding LAGEVRIO and the unfavorable impact of foreign exchange. Full-year 2023 Animal Health sales grew 1% to $5.6 billion. Excluding the unfavorable impact of foreign exchange, Animal Health sales grew 3%, primarily due to higher pricing. Full-year sales growth was also driven by higher demand for livestock products, led by poultry and swine products, partially offset by lower demand for ruminant products. Sales of BRAVECTO were $1.1 billion in 2023, which represented growth of 4%, or 5% excluding the impact of foreign exchange, primarily reflecting higher pricing. Fourth-Quarter and Full-Year Expense, EPS and Related Information The table below presents selected expense information. $ in millions GAAP Acquisition- and Divestiture- Related Costs 3 Restructuring Costs (Income) Loss From Investments in Equity Securities Non- GAAP 2 Fourth Quarter 2023 Cost of sales $3,911 $454 $117 $- $3,340 Selling, general and administrative 2,804 24 29 - 2,751 Research and development 9,628 790 - - 8,838 Restructuring costs 255 - 255 - - Other (income) expense, net 78 (35) - (61) 174 Fourth Quarter 2022 Cost of sales $3,881 $482 $38 $- $3,361 Selling, general and administrative 2,687 39 20 - 2,628 Research and development 3,775 740 - - 3,035 Restructuring costs 49 - 49 - - Other (income) expense, net (75) (69) - 80 (86) $ in millions GAAP Acquisition- and Divestiture- Related Costs 3 Restructuring Costs (Income) Loss From Investments in Equity Securities Certain Other Items Non- GAAP 2 Year Ended Dec. 31, 2023 Cost of sales $16,126 $2,018 $211 $- $- $13,897 Selling, general and administrative 10,504 86 122 - - 10,296 Research and development 30,531 819 1 - - 29,711 Restructuring costs 599 - 599 - - - Other (income) expense, net 466 (47) - (279) 573 219 Year Ended Dec. 31, 2022 Cost of sales $17,411 $2,059 $205 $- $- $15,147 Selling, general and administrative 10,042 176 94 - - 9,772 Research and development 13,548 1,676 30 - - 11,842 Restructuring costs 337 - 337 - - - Other (income) expense, net 1,501 (207) - 1,348 - 360 GAAP Expense, EPS and Related Information Gross margin was 73.3% for the fourth quarter of 2023 compared with 71.9% for the fourth quarter of 2022. The increase was primarily due to the favorable impacts of lower LAGEVRIO sales, which have a low gross margin, lower manufacturing facilities costs and product mix, partially offset by the unfavorable impacts of foreign exchange and higher restructuring costs. Gross margin was 73.2% for the full year of 2023 compared with 70.6% for the full year of 2022. The increase was primarily due to the favorable impacts of lower LAGEVRIO sales, product mix, lower manufacturing facilities costs, and lower revenue from third-party manufacturing arrangements, partially offset by the unfavorable impact of foreign exchange. Selling, general and administrative (SG&A) expenses were $2.8 billion in the fourth quarter of 2023, an increase of 4% compared with the fourth quarter of 2022. The increase was primarily due to higher administrative costs, including higher compensation and benefit costs, partially offset by lower promotional spending. Full-year 2023 SG&A expenses were $10.5 billion, an increase of 5% compared with the full year of 2022. The increase was primarily due to higher administrative costs, including higher compensation and benefit costs, and higher promotional spending, partially offset by the favorable impact of foreign exchange and lower acquisition- and divestiture-related costs. R&D expenses were $9.6 billion in the fourth quarter of 2023 compared with $3.8 billion in the fourth quarter of 2022. R&D expenses were $30.5 billion for the full year of 2023 compared with $13.5 billion for the full year of 2022. The increase in the fourth quarter and full year of 2023 reflects a $5.5 billion charge for the collaboration with Daiichi Sankyo, and higher development costs due to spending on clinical programs, including newly acquired programs, as well as higher compensation and benefit costs (reflecting in part increased headcount). The increase in R&D expenses for the full year was also due to charges of $11.4 billion in the aggregate for the acquisitions of Prometheus Biosciences, Inc. (Prometheus) and Imago BioSciences, Inc. (Imago). The increase in R&D expenses for the full year was partially offset by lower intangible asset impairment charges in 2023 and charges of $690 million in the aggregate in 2022 for collaboration and licensing agreements with Moderna, Inc. (Moderna), Orna Therapeutics (Orna) and Orion Corporation (Orion). Other (income) expense, net, was $78 million of expense in the fourth quarter of 2023 compared with $75 million of income in the fourth quarter of 2022, primarily due to higher exchange losses and higher net interest expense, partially offset by net gains from investments in equity securities for the fourth quarter of 2023 compared with net losses from investments in equity securities for the fourth quarter of 2022, and lower pension settlement costs. Other (income) expense, net, was $466 million of expense in the full year of 2023 compared with $1.5 billion of expense in the full year of 2022, primarily due to net gains from investments in equity securities in 2023 compared with net losses from investments in equity securities in 2022, and lower pension settlement costs, partially offset by a $572.5 million charge in 2023 related to settlements with certain plaintiffs in the Zetia antitrust litigation. The effective tax rate was 40.1% for the fourth quarter of 2023 compared with 14.1% in the fourth quarter of 2022. The effective tax rate for the fourth quarter of 2023 includes a 29.2 percentage point impact resulting from the charge for the Daiichi Sankyo collaboration. The effective tax rate was 80.0% for the full year of 2023 compared with 11.7% for the full year of 2022. The full-year 2023 effective tax rate reflects an aggregate 65.6 percentage point unfavorable impact, resulting from charges for asset acquisitions (for which no tax benefits were recognized) as well as the charge for the Daiichi Sankyo collaboration. GAAP loss per share was $0.48 for the fourth quarter of 2023 compared with EPS of $1.18 for the fourth quarter of 2022, primarily driven by the charge in 2023 related to the collaboration with Daiichi Sankyo, the unfavorable impact of foreign exchange and higher restructuring costs, partially offset by a beneficial impact from the tax rate and operational strength in the business. GAAP EPS was $0.14 for the full year of 2023 compared with EPS of $5.71 for the full year of 2022. The EPS decline in 2023 was primarily due to higher charges for certain business development transactions, the unfavorable impact of foreign exchange and the tax rate, as well as a charge related to settlements with certain plaintiffs in the Zetia antitrust litigation, partially offset by the beneficial impacts of operational strength in the business, better performance from equity investments and lower intangible asset impairment charges. Non-GAAP Expense, EPS and Related Information Non-GAAP gross margin was 77.2% for the fourth quarter of 2023 compared with 75.7% for the fourth quarter of 2022. Non-GAAP gross margin was 76.9% for the full year of 2023 compared with 74.4% for the full year of 2022. The non-GAAP gross margin improvement in the fourth quarter and full year of 2023 was primarily due to the favorable impacts of lower LAGEVRIO sales, which have a low gross margin, product mix, and lower manufacturing facilities costs. The increase in non-GAAP gross margin for the full year was also due to lower revenue from third-party manufacturing arrangements. The non-GAAP gross margin improvement in the fourth quarter and full year of 2023 was partially offset by the unfavorable impact of foreign exchange. Non-GAAP SG&A expenses were $2.8 billion for the fourth quarter of 2023 compared with $2.6 billion for the fourth quarter of 2022. The increase was primarily due to higher administrative costs, including higher compensation and benefit costs, partially offset by lower promotional spending. Full-year 2023 non-GAAP SG&A expenses were $10.3 billion, an increase of 5% compared with the full year of 2022. The increase was primarily due to higher administrative costs, including higher compensation and benefit costs, and higher promotional spending, partially offset by the favorable impact of foreign exchange. Non-GAAP R&D expenses were $8.8 billion in the fourth quarter of 2023 compared with $3.0 billion in the fourth quarter of 2022. Non-GAAP R&D expenses were $29.7 billion for the full year of 2023 compared with $11.8 billion for the full year of 2022. The increase in the fourth quarter and full year of 2023 reflects a $5.5 billion charge for the collaboration with Daiichi Sankyo, and higher development costs due to spending on clinical programs, including newly acquired programs, as well as higher compensation and benefit costs (reflecting in part increased headcount). The increase in non-GAAP R&D expenses for the full year was also due to charges of $11.4 billion in the aggregate for the acquisitions of Prometheus and Imago. The increase in R&D expenses for the full year was partially offset by charges of $690 million in the aggregate in 2022 for collaboration and licensing agreements with Moderna, Orna and Orion. Non-GAAP other (income) expense, net, was $174 million of expense in the fourth quarter of 2023 compared with $86 million of income in the fourth quarter of 2022, primarily due to higher exchange losses and higher net interest expense, partially offset by lower pension settlement costs. Non-GAAP other (income) expense, net, was $219 million of expense in the full year of 2023 compared with $360 million of expense in the full year of 2022, primarily due to lower pension settlement costs. The non-GAAP effective tax rate was 114.2% for the fourth quarter of 2023 compared with 15.6% in the fourth quarter of 2022. The non-GAAP effective tax rate for the fourth quarter of 2023 includes a 101.1 percentage point unfavorable impact resulting from the charge for the Daiichi Sankyo collaboration. The non-GAAP effective tax rate was 35.8% for the full year of 2023 compared with 14.2% for the full year of 2022. The full-year 2023 non-GAAP effective tax rate reflects an aggregate 21.2 percentage point unfavorable impact, resulting from charges for asset acquisitions (for which no benefits were recognized) as well as the charge for the Daiichi Sankyo collaboration. Non-GAAP EPS was $0.03 for the fourth quarter of 2023 compared with $1.62 for the fourth quarter of 2022. The non-GAAP EPS decline in the fourth quarter was primarily due to the charge in 2023 related to the collaboration with Daiichi Sankyo and the unfavorable impact of foreign exchange, partially offset by a beneficial impact from the tax rate and operational strength in the business. Non-GAAP EPS was $1.51 for the full year of 2023 compared with $7.48 for the full year of 2022. The non-GAAP EPS decline for the full year was primarily due to higher charges for certain business development transactions, the unfavorable impact of foreign exchange and the tax rate, partially offset by operational strength in the business. A reconciliation of GAAP to non-GAAP net (loss) income and (loss) earnings per share is provided in the table that follows. Fourth Quarter Year Ended $ in millions, except EPS amounts 2023 2022 Dec. 31, 2023 Dec. 31, 2022 EPS GAAP EPS $(0.48) $1.18 $0.14 $5.71 Difference 0.51 0.44 1.37 1.77 Non-GAAP EPS that excludes items listed below 2 $0.03 $1.62 $1.51 $7.48 Net (Loss) Income GAAP net (loss) income 1 $(1,226) $3,017 $365 $14,519 Difference 1,292 1,112 3,472 4,486 Non-GAAP net income that excludes items listed below 1,2 $66 $4,129 $3,837 $19,005 Excluded Items: Acquisition- and divestiture-related costs 3 $1,233 $1,192 $2,876 $3,704 Restructuring costs 401 107 933 666 (Income) loss from investments in equity securities (61) 80 (279) 1,348 Charge for Zetia antitrust litigation settlements - - 573 - Increase to net loss/decrease to net income before taxes 1,573 1,379 4,103 5,718 Estimated income tax (benefit) expense (281) (267) (631) (1,232) Increase to net loss/decrease to net income $1,292 $1,112 $3,472 $4,486 2024 Restructuring Program Merck recently approved a new restructuring program (2024 Restructuring Program) intended to continue the optimization of the company’s Human Health global manufacturing network as the future pipeline shifts to new modalities, and also to optimize the Animal Health global manufacturing network to improve supply reliability and increase efficiency. The company recorded charges in its GAAP results of $190 million related to the 2024 Restructuring Program for the fourth quarter and full year of 2023. Pipeline and Portfolio Highlights In the fourth quarter, Merck continued to make significant progress advancing its broad portfolio and pipeline across key therapeutic areas, representing continued momentum toward addressing patient needs. In oncology, Merck received multiple U.S. Food and Drug Administration (FDA) approvals, including KEYTRUDA plus Padcev for the first-line treatment of adult patients with locally advanced or metastatic urothelial cancer and WELIREG for the treatment of certain patients with previously treated advanced RCC, among other approvals. The FDA also accepted and granted Priority Review to Merck and Daiichi Sankyo’s Biologics License Application (BLA) for patritumab deruxtecan for the treatment of certain patients with previously treated locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC). The FDA set a Prescription Drug User Fee Act (PDUFA), or target action, date of June 26, 2024. In addition, Merck showed meaningful progress in its robust oncology pipeline, initiating Phase 3 trials for four investigational medicines, including bomedemstat (LSD1 inhibitor), nemtabrutinib (BTK inhibitor), MK-2870 (anti-TROP2 antibody-drug conjugate) and MK-5684 (CYP11A1 inhibitor). In vaccines, Merck received Priority Review from the FDA for a BLA for V116, the company’s investigational, 21-valent pneumococcal conjugate vaccine specifically designed to protect adults, based on results from multiple Phase 3 trials. The FDA set a PDUFA date of June 17, 2024. If approved, V116 would be the first pneumococcal conjugate vaccine to include serotypes responsible for approximately 83 percent of adult invasive pneumococcal disease in individuals 65 and older, according to U.S. Centers for Disease Control and Prevention data from 2018-2021. In hospital acute care, the European Commission (EC) approved PREVYMIS for prevention of cytomegalovirus (CMV) disease in high-risk adult kidney transplant recipients and extended 200-day dosing in adult hematopoietic stem cell transplant (HSCT) recipients who are at high risk for late CMV infection and disease. Merck continued to augment its pipeline through business development, and in January 2024, entered into a definitive agreement to acquire Harpoon Therapeutics, Inc. (Harpoon), for an approximate total equity value of $680 million, further diversifying its oncology pipeline. Notable recent news releases on Merck’s pipeline and portfolio are provided in the table that follows. Oncology FDA Approved Expanded Indication for KEYTRUDA Plus Padcev as First-Line Treatment for Adult Patients With Locally Advanced or Metastatic Urothelial Cancer, Based on Results From Phase 3 KEYNOTE-A39 Trial (Read Announcement) FDA Approved Merck’s WELIREG as Treatment for Patients With Advanced RCC Following a PD-1 or PD-L1 Inhibitor and a VEGF-TKI, Based on Results From LITESPARK-005 Trial (Read Announcement) FDA Approved Merck’s KEYTRUDA Plus Chemoradiotherapy as Treatment for Patients With FIGO 2014 Stage III-IVA Cervical Cancer, Based on Results From Phase 3 KEYNOTE-A18 Trial (Read Announcement) FDA Approved Merck’s KEYTRUDA Plus Chemotherapy as First-Line Treatment for Locally Advanced Unresectable or Metastatic HER2-Negative Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma, Based on Results From Phase 3 KEYNOTE-859 Trial (Read Announcement) FDA Approved Merck’s KEYTRUDA Plus Gemcitabine and Cisplatin as Treatment for Patients With Locally Advanced Unresectable or Metastatic Biliary Tract Cancer, Based on Results From Phase 3 KEYNOTE-966 Trial (Read Announcement) EC Approved KEYTRUDA Plus Chemotherapy for New First-Line Indications in Advanced HER2-Negative Gastric or GEJ Adenocarcinoma in Tumors Expressing PD-L1 (CPS ≥1) and Advanced Biliary Tract Cancer, Based on Results From Phase 3 KEYNOTE-859 and KEYNOTE-966 Trials (Read Announcement) FDA Granted Priority Review to Merck and Daiichi Sankyo’s BLA for Patritumab Deruxtecan for the Treatment of Certain Patients With Previously Treated Locally Advanced or Metastatic EGFR-Mutated NSCLC, Based on Results From Phase 2 HERTHENA-Lung01 Trial; FDA Set PDUFA Date of June 26, 2024 (Read announcement) Merck Announced Phase 3 Trial Initiations for Bomedemstat, Nemtabrutinib, MK-2870 and MK-5684, Four Investigational Candidates From Promising Hematology and Oncology Pipeline (Read announcement) Merck and Moderna Initiated INTerpath-002, a Phase 3 Study Evaluating V940 (mRNA-4157) in Combination With KEYTRUDA for Adjuvant Treatment of Patients With Certain Types of Resected NSCLC (Read Announcement) KEYTRUDA Reduced the Risk of Death by 38% Versus Placebo as Adjuvant Therapy for Patients With RCC at an Increased Risk of Recurrence Following Nephrectomy, Based on Results From Phase 3 KEYNOTE-564 Trial (Read Announcement) KEYTRUDA Significantly Improved Disease-Free Survival as Adjuvant Therapy Versus Observation in High-Risk Patients With Localized Muscle-Invasive and Locally Advanced Urothelial Carcinoma After Surgery, Based on Results From Phase 3 AMBASSADOR/KEYNOTE-123 Trial (Read Announcement) Moderna and Merck Announced V940 (mRNA-4157) in Combination With KEYTRUDA Demonstrated Continued Improvement in Recurrence-Free Survival and Distant Metastasis-Free Survival in Patients With High-Risk Stage III/IV Melanoma Following Complete Resection Versus KEYTRUDA at Three Years, Based on Results From Phase 2b Randomized KEYNOTE-942/mRNA-4157-P201 Study (Read Announcement) Vaccines FDA Granted Priority Review to Merck’s New BLA for V116, an Investigational, 21-valent Pneumococcal Conjugate Vaccine Specifically Designed to Protect Adults, Based on Results From Multiple Phase 3 Trials; FDA Set PDUFA Date of June 17, 2024 (Read Announcement) Merck’s V116, an Investigational, 21-valent Pneumococcal Conjugate Vaccine Specifically Designed to Protect Adults, Demonstrated Superior Immunogenicity for 10 of 11 Unique Serotypes Compared to PCV20 in Adults 50 Years of Age and Older, Based on Results From Phase 3 STRIDE-3 Trial (Read Announcement) Full-Year 2024 Financial Outlook The following table summarizes the company’s full-year financial outlook. Full Year 2024 Sales * $62.7 to $64.2 billion Non-GAAP gross margin 2 Approximately 80.5% Non-GAAP operating expenses 2** $25.1 to $26.1 billion Non-GAAP other (income) expense, net 2 Approximately $200 million expense Non-GAAP effective tax rate 2 14.5% to 15.5% Non-GAAP EPS 2*** $8.44 to $8.59 Share count (assuming dilution) Approximately 2.54 billion *The company does not have any non-GAAP adjustments to sales. **Includes approximately $650 million of R&D expense related to the recently announced Harpoon acquisition, which is expected to close in the first half of 2024. Outlook does not assume any additional significant potential business development transactions. ***Includes a one-time charge of approximately $0.26 per share related to the Harpoon acquisition. Merck has not provided a reconciliation of forward-looking non-GAAP gross margin, non-GAAP operating expenses, non-GAAP other (income) expense, net, non-GAAP effective tax rate and non-GAAP EPS to the most directly comparable GAAP measures, given it cannot predict with reasonable certainty the amounts necessary for such a reconciliation, including intangible asset impairment charges, legal settlements, and income and losses from investments in equity securities either owned directly or through ownership interests in investment funds, without unreasonable effort. These items are inherently difficult to forecast and could have a significant impact on the company’s future GAAP results. Merck anticipates full-year 2024 sales to be between $62.7 billion and $64.2 billion, including a negative impact of foreign exchange of approximately 2% at mid-January 2024 exchange rates. The negative impact is primarily due to the devaluation of the Argentine peso, which the company expects will largely be offset by inflation-related price increases, consistent with market practice. The outlook for operating expenses reflects incremental R&D spending expected to be incurred to advance the development of promising programs related to the acquisitions of Prometheus, Imago and Harpoon, as well as the collaborations with Daiichi Sankyo and Kelun-Biotech. Merck’s full-year non-GAAP effective income tax rate is expected to be between 14.5% and 15.5%. Merck expects full-year 2024 non-GAAP EPS to be between $8.44 and $8.59, including a negative impact of foreign exchange of approximately $0.25 per share. In 2023, non-GAAP EPS of $1.51 was negatively impacted by charges of $6.21 per share related to certain acquisitions and collaboration agreements. In early January 2024, Merck announced the acquisition of Harpoon, which is expected to close in the first half of 2024, and result in a non-tax deductible charge of approximately $650 million of R&D expense included in non-GAAP results. The impact of the transaction on expected full-year non-GAAP EPS is approximately $0.26 per share, which is included in the 2024 outlook. Consistent with past practice, the financial outlook does not assume additional significant potential business development transactions. Earnings Conference Call Investors, journalists and the general public may access a live audio webcast of the earnings conference call on Thursday, Feb. 1, at 9 a.m. ET via this weblink . A replay of the webcast, along with the sales and earnings news release, supplemental financial disclosures, prepared remarks and slides highlighting the results, will be available at www.merck.com . All participants may join the call by dialing (800) 779-6561 (U.S. and Canada Toll-Free) or (773) 756-4619 and using the access code 5958465. About Merck At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on X (formerly Twitter ) , Facebook , Instagram , YouTube and LinkedIn . Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA This news release of Merck & Co., Inc., Rahway, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of the global outbreak of novel coronavirus disease (COVID-19); the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions. The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2022, and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site ( www.sec.gov ). Appendix Generic product names are provided below. Pharmaceutical BRIDION (sugammadex) GARDASIL ( Human Papillomavirus Quadrivalent [Types 6, 11, 16 and 18] Vaccine, Recombinant ) GARDASIL 9 (Human Papillomavirus 9-valent Vaccine, Recombinant) JANUMET (sitagliptin and metformin HCl) JANUVIA (sitagliptin) KEYTRUDA (pembrolizumab) LAGEVRIO (molnupiravir) Lenvima (lenvatinib) Lynparza ( olaparib) M-M-R II (Measles, Mumps and Rubella Virus Vaccine Live) PNEUMOVAX 23 (Pneumococcal Vaccine Polyvalent) PREVYMIS ( letermovir ) PROQUAD (Measles, Mumps, Rubella and Varicella Virus Vaccine Live) ROTATEQ (Rotavirus Vaccine, Live, Oral, Pentavalent) VARIVAX (Varicella Virus Vaccine Live) VAXNEUVANCE ( Pneumococcal 15-valent Conjugate Vaccine ) WELIREG ( belzutifan ) Animal Health BRAVECTO (fluralaner) ________________________________ 1 Net (loss) income attributable to Merck & Co., Inc. 2 Merck is providing certain 2023 and 2022 non-GAAP information that excludes certain items because of the nature of these items and the impact they have on the analysis of underlying business performance and trends. Management believes that providing this information enhances investors’ understanding of the company’s results because management uses non-GAAP results to assess performance. Management uses non-GAAP measures internally for planning and forecasting purposes and to measure the performance of the company along with other metrics. In addition, senior management’s annual compensation is derived in part using a non-GAAP pre-tax income metric. This information should be considered in addition to, but not as a substitute for or superior to, information prepared in accordance with GAAP. For a description of the non-GAAP adjustments, see Table 2a attached to this release. 3 Includes expenses for the amortization of intangible assets and purchase accounting adjustments to inventories recognized as a result of acquisitions of businesses, intangible asset impairment charges and expense or income related to changes in the estimated fair value measurement of liabilities for contingent consideration. R&D expenses include intangible asset impairment charges of $779 million in both the fourth quarter and full year of 2023 related to gefapixant and $780 million and $1.7 billion in the fourth quarter and full year of 2022, respectively, largely related to nemtabrutinib. Also includes integration, transaction and certain other costs associated with acquisitions and divestitures, as well as amortization of intangible assets related to collaborations and licensing arrangements. MERCK & CO., INC. CONSOLIDATED STATEMENT OF OPERATIONS - GAAP (AMOUNTS IN MILLIONS, EXCEPT PER SHARE FIGURES) (UNAUDITED) Table 1 GAAP % Change GAAP % Change 4Q23 4Q22 Full Year 2023 Full Year 2022 Sales $ 14,630 $ 13,830 6 % $ 60,115 $ 59,283 1 % Costs, Expenses and Other Cost of sales 3,911 3,881 1 % 16,126 17,411 -7 % Selling, general and administrative 2,804 2,687 4 % 10,504 10,042 5 % Research and development 9,628 3,775 * 30,531 13,548 * Restructuring costs 255 49 * 599 337 78 % Other (income) expense, net 78 (75 ) * 466 1,501 -69 % (Loss) Income Before Taxes (2,046 ) 3,513 * 1,889 16,444 -89 % Income Tax (Benefit) Provision (821 ) 495 1,512 1,918 Net (Loss) Income (1,225 ) 3,018 * 377 14,526 -97 % Less: Net Income Attributable to Noncontrolling Interests 1 1 12 7 Net (Loss) Income Attributable to Merck & Co., Inc. $ (1,226 ) $ 3,017 * $ 365 $ 14,519 -97 % (Loss) Earnings per Common Share Assuming Dilution (1) $ (0.48 ) $ 1.18 * $ 0.14 $ 5.71 -98 % Average Shares Outstanding Assuming Dilution (1) 2,533 2,548 2,547 2,542 Tax Rate 40.1 % 14.1 % 80.0 % 11.7 % * 100% or greater (1) Because the company recorded a net loss in the fourth quarter of 2023, no potential dilutive common shares were used in the computation of loss per common share assuming dilution as the effect would have been anti-dilutive. MERCK & CO., INC. FOURTH QUARTER AND FULL YEAR 2023 GAAP TO NON-GAAP RECONCILIATION (AMOUNTS IN MILLIONS, EXCEPT PER SHARE FIGURES) (UNAUDITED) Table 2a GAAP Acquisition and Divestiture-Related Costs (1) Restructuring Costs (2) (Income) Loss from Investments in Equity Securities Certain Other Items Adjustment Subtotal Non-GAAP Fourth Quarter Cost of sales $ 3,911 454 117 571 $ 3,340 Selling, general and administrative 2,804 24 29 53 2,751 Research and development 9,628 790 790 8,838 Restructuring costs 255 255 255 – Other (income) expense, net 78 (35 ) (61 ) (96 ) 174 Loss Before Taxes (2,046 ) (1,233 ) (401 ) 61 (1,573 ) (473 ) Income Tax Provision (Benefit) (821 ) (227 ) (4 ) (67 ) (4 ) 13 (4 ) (281 ) (540 ) Net (Loss) Income (1,225 ) (1,006 ) (334 ) 48 (1,292 ) 67 Net (Loss) Income Attributable to Merck & Co., Inc. (1,226 ) (1,006 ) (334 ) 48 (1,292 ) 66 (Loss) Earnings per Common Share Assuming Dilution (5) $ (0.48 ) (0.40 ) (0.13 ) 0.02 (0.51 ) $ 0.03 Tax Rate 40.1 % 114.2 % Full Year Cost of sales $ 16,126 2,018 211 2,229 $ 13,897 Selling, general and administrative 10,504 86 122 208 10,296 Research and development 30,531 819 1 820 29,711 Restructuring costs 599 599 599 – Other (income) expense, net 466 (47 ) (279 ) 573 (3 ) 247 219 Income Before Taxes 1,889 (2,876 ) (933 ) 279 (573 ) (4,103 ) 5,992 Income Tax Provision (Benefit) 1,512 (476 ) (4 ) (155 ) (4 ) 60 (4 ) (60 ) (4 ) (631 ) 2,143 Net Income 377 (2,400 ) (778 ) 219 (513 ) (3,472 ) 3,849 Net Income Attributable to Merck & Co., Inc. 365 (2,400 ) (778 ) 219 (513 ) (3,472 ) 3,837 Earnings per Common Share Assuming Dilution $ 0.14 (0.94 ) (0.31 ) 0.08 (0.20 ) (1.37 ) $ 1.51 Tax Rate 80.0 % 35.8 % Only the line items that are affected by non-GAAP adjustments are shown. Merck is providing certain non-GAAP information that excludes certain items because of the nature of these items and the impact they have on the analysis of underlying business performance and trends. Management believes that providing non-GAAP information enhances investors’ understanding of the company’s results because management uses non-GAAP measures to assess performance. Management uses non-GAAP measures internally for planning and forecasting purposes and to measure the performance of the company along with other metrics. In addition, senior management’s annual compensation is derived in part using a non-GAAP pretax income metric. The non-GAAP information presented should be considered in addition to, but not as a substitute for or superior to, information prepared in accordance with GAAP. (1) Amounts included in cost of sales primarily reflect expenses for the amortization of intangible assets. Amounts included in selling, general and administrative expenses reflect integration, transaction and certain other costs related to acquisitions and divestitures. Amounts included in research and development expenses primarily reflect a $779 million in-process research and development (IPR&D) impairment charge related to gefapixant, which was obtained as part of the 2016 Afferent Pharmaceuticals acquisition, and expenses for the amortization of intangible assets. Amounts included in other (income) expense, net, primarily reflect royalty income related to the prior termination of the Sanofi-Pasteur MSD joint venture. Additionally, other (income) expense, net, for the full year includes a $37 million loss on the sale of a business. (2) Amounts primarily include employee separation costs and accelerated depreciation associated with facilities to be closed or divested related to activities under the company's formal restructuring programs. (3) Reflects a charge related to settlements with certain plaintiffs in the Zetia antitrust litigation. (4) Represents the estimated tax impacts on the reconciling items based on applying the statutory rate of the originating territory of the non-GAAP adjustments. (5) Because the company recorded a net loss in the fourth quarter of 2023, no potential dilutive common shares were used in the computation of loss per common share assuming dilution as the effect would have been anti-dilutive. MERCK & CO., INC. FRANCHISE / KEY PRODUCT SALES (AMOUNTS IN MILLIONS) (UNAUDITED) Table 3 2023 2022 4Q Full Year 1Q 2Q 3Q 4Q Full Year 1Q 2Q 3Q 4Q Full Year Nom % Ex-Exch % Nom % Ex-Exch % TOTAL SALES (1) $14,487 $15,035 $15,962 $14,630 $60,115 $15,901 $14,593 $14,959 $13,830 $59,283 6 7 1 4 PHARMACEUTICAL 12,721 13,457 14,263 13,141 53,583 14,107 12,756 12,963 12,180 52,005 8 8 3 5 Oncology Keytruda 5,795 6,271 6,338 6,608 25,011 4,809 5,252 5,426 5,450 20,937 21 22 19 21 Alliance Revenue – Lynparza (2) 275 310 299 315 1,199 266 275 284 292 1,116 8 8 7 9 Alliance Revenue – Lenvima (2) 232 242 260 226 960 227 231 202 216 876 5 5 10 11 Welireg 42 50 54 72 218 18 27 38 40 123 79 78 77 77 Alliance Revenue – Reblozyl (3) 43 47 52 70 212 52 33 39 41 166 69 69 28 28 Vaccines (4) Gardasil / Gardasil 9 1,972 2,458 2,585 1,871 8,886 1,460 1,674 2,294 1,470 6,897 27 27 29 33 ProQuad / M-M-R II / Varivax 528 582 713 545 2,368 470 578 668 526 2,241 4 3 6 6 RotaTeq 297 131 156 185 769 216 173 256 139 783 34 33 -2 -1 Vaxneuvance 106 168 214 176 665 5 12 16 138 170 28 26 * * Pneumovax 23 96 92 140 85 412 173 153 131 145 602 -42 -43 -32 -31 Vaqta 40 42 69 29 180 36 35 64 39 173 -24 -25 4 4 Hospital Acute Care Bridion 487 502 424 429 1,842 395 426 423 441 1,685 -3 -3 9 11 Prevymis 129 143 157 175 605 94 103 114 118 428 49 49 41 43 Dificid 65 76 74 87 302 52 66 77 67 263 30 30 15 15 Zerbaxa 50 54 53 61 218 30 46 43 49 169 25 23 29 30 Noxafil 60 55 51 46 213 57 60 62 58 238 -21 -16 -11 -4 Primaxin 80 53 41 39 213 58 64 63 54 239 -28 -28 -11 -6 Cardiovascular Alliance Revenue - Adempas/Verquvo (5) 99 68 92 108 367 72 98 88 82 341 31 31 8 8 Adempas (6) 59 65 65 66 255 61 63 57 57 238 15 11 7 8 Virology Lagevrio 392 203 640 193 1,428 3,247 1,177 436 825 5,684 -77 -76 -75 -74 Isentress / Isentress HD 123 136 119 105 483 158 147 161 167 633 -37 -37 -24 -23 Neuroscience Belsomra 56 63 58 54 231 69 69 62 59 258 -8 -6 -11 -6 Immunology Simponi 180 180 179 171 710 186 181 173 166 706 3 -2 1 - Remicade 51 48 45 43 187 61 53 49 44 207 -1 -2 -9 -8 Diabetes (7) Januvia 551 511 581 547 2,189 779 756 717 561 2,813 -2 -2 -22 -20 Janumet 329 354 255 240 1,177 454 476 417 353 1,700 -32 -32 -31 -29 Other Pharmaceutical (8) 584 553 549 595 2,283 602 528 603 583 2,319 2 2 -2 - ANIMAL HEALTH 1,491 1,456 1,400 1,278 5,625 1,482 1,467 1,371 1,230 5,550 4 4 1 3 Livestock 849 807 874 808 3,337 832 826 829 814 3,300 -1 - 1 4 Companion Animal 642 649 526 470 2,288 650 641 542 416 2,250 13 12 2 3 Other Revenues (9) 275 122 299 211 907 312 370 625 420 1,728 -50 -1 -48 -15 *200% or greater Sum of quarterly amounts may not equal year-to-date amounts due to rounding. (1) Only select products are shown. (2) Alliance Revenue represents Merck’s share of profits, which are product sales net of cost of sales and commercialization costs. (3) Alliance Revenue represents royalties and a milestone payment of $20 million received in the first quarter of 2022. (4) Total Vaccines sales were $3,133 million, $3,557 million, $4,002 million and $2,962 million in the first, second, third and fourth quarter of 2023, respectively, and $2,481 million, $2,709 million, $3,552 million and $2,554 million in the first, second, third and fourth quarter of 2022, respectively. (5) Alliance Revenue represents Merck's share of profits from sales in Bayer's marketing territories, which are product sales net of cost of sales and commercialization costs. (6) Net product sales in Merck's marketing territories. (7) Total Diabetes sales were $950 million, $951 million, $924 million and $876 million in the first, second, third and fourth quarter of 2023, respectively, and $1,305 million, $1,300 million, $1,231 million and $1,012 million in the first, second, third and fourth quarter of 2022, respectively. (8) Includes Pharmaceutical products not individually shown above. (9) Other Revenues are comprised primarily of revenues from third-party manufacturing arrangements and miscellaneous corporate revenues, including revenue-hedging activities. Other Revenues related to the receipt of upfront and milestone payments for out-licensed products were $51 million, $3 million and $65 million in the first, second and third quarter of 2023, respectively, and $114 million, $32 million, $10 million and $10 million in the first, second, third and fourth quarter of 2022, respectively.

随着水痘-带状疱疹病毒（VZV）的全基因组序列测定、VZV感染性克隆技术成功突破，有效预防疫苗不断出现，并被证实其良好的有效性及安全性，水痘已成为一种可通过特异性免疫预防的疾病。本文将从VZV的基因组学结构、流行病学特点、水痘疫苗与带状疱疹疫苗研究应用进展等方面进行阐述，为疾病一级预防提供参考。水痘-带状疱疹病毒（varicella-zoster virus，VZV）属于疱疹病毒科，α-疱疹病毒亚科，有囊膜的双链DNA病毒，感染后可引起水痘（varicella；chickenpox）和带状疱疹（herpes zoster，HZ）两种疾病，全球感染率>90%。原发性VZV感染表现为水痘，多见于儿童，水痘痊愈后VZV能在宿主的感觉神经节长期潜伏，当宿主细胞免疫力下降时被再次激活，表现为带状疱疹。一项全球疾病负担研究估计，2019年全球VZV感染新发病例为8 396万例，较1990年上升17.85%。全球的HZ发病率也逐年上升，每年造成的生产力损失给全社会带来数十亿美元的损失。一、VZV的基因组学结构Davison和Scott研究表明，VZV病毒DNA包括124 884 bp，相对分子质量约为80 MDa（80×106），G+C含量达到46%。VZV基因组由两个共价键连接的长片段（L）和短片段（S）DNA组成。依据VZV的5个小重复片段区域（R1~R5）中串联重复单位数的差异，可以区分毒株亚型。VZV只有一个血清型，但有多个基因型。目前，已被证实的有5个基因型，另有2个待全基因测序证实。欧洲、美国和新西兰主要流行Clade1和Clade3，亚洲流行毒株以Clade2为主，非洲则以Clade5为主。中国VZV的优势基因型为Clade2，但在我国新疆和西藏发现Clade4和Clade5也为优势进化分支，与Clade2持续循环流行。二、VZV流行病学VZV是一种具有高度传染性的疱疹病毒，感染后常表现为儿童的水痘和中老年人再次激活后的带状疱疹。VZV发病年龄存在地区差异，在一些热带地区，感染平均年龄后移。初次感染后，VZV潜伏于感觉神经节内，在机体细胞免疫力低下的条件下可被再次激活。1.水痘流行病学：VZV引起的水痘为世界范围流行的疾病。在温带气候地区，几乎所有人在青年期均已被感染，其中学龄前或刚入小学的儿童水痘发病率最高，冬、春季为水痘发病高峰。热带地区的发病高峰是最寒冷、干燥的月份，每隔2~5 年出现一次周期性暴发。水痘为自限性疾病，但会因继发细菌感染引起的严重并发症。成年人患水痘，出现脑炎并发症的发生率是儿童的7倍，肺炎并发症发生率可达20%~30%，严重时可导致患者死亡。由于缺乏明确的技术要求和法律法规，中国尚未将水痘纳入法定传染病报告管理，仅部分地区如上海、北京、天津、山东、宁波等省市地区将水痘纳入地方重点监测疾病，按照国家法定丙类传染病进行报告和管理。根据2007年在山东、甘肃和湖南三省开展的入户调查结果估算，中国全人口水痘发病率为358/10万，但由于监测系统尚未全面建立，我国水痘发病病例数存在漏报，发病率被严重低估。2. 带状疱疹流行病学：体内潜伏VZV病毒再激活表现为带状疱疹，它经常发生于老年人和免疫功能低下的成年人中，50 岁以后尤为明显，这与年龄增长导致的细胞免疫功能减退有关。一项系统综述研究发现，欧美、亚太区域的带状疱疹发病率为3~5/1 000人年，≥60岁老年人发病率分别为6~12/1 000人年，随着人口老龄化的加剧，带状疱疹的公共卫生问题将会越来越突出。三、水痘疫苗与带状疱疹疫苗研究进展接种疫苗是预防由VZV引起的水痘与带状疱疹的最经济有效措施。目前已上市的水痘疫苗有各有两种水痘减毒活疫苗、水痘联合疫苗和带状疱疹疫苗，随着对VZV病毒认识的深入及分子生物学技术的发展，灭活疫苗、蛋白亚单位疫苗、病毒载体疫苗、DNA疫苗等技术研发路线也取得了一定进展，但是，距离上市应用仍还有很长的路要走。因此，采用新技术，研制更加安全有效的疫苗是VZV防控研究的重要领域。一水痘疫苗的研究进展1.水痘减毒活疫苗/水痘联合疫苗：水痘减毒活疫苗是最早获准用于预防由人类疱疹病毒引起的疾病的疫苗。虽然VZV-Oka减毒活疫苗具有良好的免疫保护效果，但是VZV属于疱疹病毒属，有在感觉神经节潜伏的危险，此外，VZV减毒活疫苗的毒株可以在免疫缺陷人群、易感接触者中传播。目前在世界各地广泛使用的水痘疫苗均是1983年被世界卫生组织（World Health Organization，WHO）推荐的V-Oka疫苗株。Oka株疫苗的起源可追溯到1952年，Weller和Stoddard通过细胞培养获得VZV，并首次报道疱疹病毒体外增殖成功。1971年，日本学者Takahashi等从1例3岁的水痘患儿水疱液中分离得到Oka疫苗株的亲本株，并培养获得了VZV减毒疫苗株V-Oka，成为了首个水痘减毒活疫苗。由于缺乏合适的动物模型，Oka疫苗株研究都在人群中进行，其最早于日本完成。此后，其他国家也陆续开展了水痘疫苗的研究。早期的有效性临床研究中，美国采用了随机、双盲、安慰剂对照的方法，证明该疫苗在预防这一健康儿童群体的水痘方面有效率为100%。芬兰后采用相同的方法研究显示Oka疫苗的有效率>90%。水痘疫苗于1984年在德国和瑞典首次获得许可，1988年在日本和韩国获得许可。1995年，美国食品和药物监督管理局（Food and Drug Administration，FDA）批准水痘减毒活疫苗（Varivax，Oka/Merk）用于12~18月龄儿童的常规免疫，后又推广到12月龄~12岁的儿童进行常规免疫。1997至2005年间的监测结果显示，Varivax疫苗对于水痘的预防与控制是安全有效的。美国水痘疫苗在19~35个月儿童水痘疫苗1剂的接种率从27%提高至88%。高疫苗接种率使美国水痘病例数减少了71%~84%，水痘相关住院率减少了88%，1~4岁儿童水痘相关死亡率减少了92%。相关研究证实，国产水痘疫苗和进口水痘疫苗免疫原性无统计学差异；在安全性方面，除接种后发热率稍高外，其他局部和全身反应性良好。李娜等系统评价发现，水痘疫苗免疫成功率为92.12%，平均抗体滴度为1∶177.95，不良反应发生率为11.54%，表明国产水痘疫苗的免疫原性良好，安全性可靠，能有效降低儿童患水痘的风险。在接受1剂次水痘疫苗的学龄儿童中水痘突破性病例的发生率高达15%，水痘暴发的年龄高峰也由疫苗接种前的3~6岁后移至疫苗接种后的9~11岁。为了减少水痘突破病例的发生率，2006年6月美国免疫实施咨询委员会（Advisory Committee on Immunization Practices，ACIP）建议，对所有4~6岁儿童增加接种第2剂水痘疫苗；对≥13岁无VZV疫苗免疫史者，应间隔4~8周接种两剂水痘疫苗。通过接种2剂次疫苗，可维持更高、更持久的抗体水平。同时，发现第2剂水痘疫苗的不良反应发生率低于第1剂。WHO建议水痘构成重要公共卫生问题的国家应考虑将水痘疫苗纳入常规儿童免疫计划，在 12~18 个月龄时接种第一剂。塞浦路斯、德国、希腊、卢森堡等欧洲国家也已将两剂次水痘疫苗纳入了国家免疫规划。德国建议11~14个月间接种3联疫苗——麻疹、腮腺炎、风疹，以及水痘疫苗。一岁半左右再巩固一针。比利时推荐1~12岁儿童1剂次接种，13岁以上的儿童、青少年和成人2剂次接种，间隔6~10周，1997年水痘疫苗在中国上市，为第二类疫苗自愿接种，免疫程序为满18月龄接种第1剂，满4岁接种第2剂。近几年，北京、上海、天津等省市地区已陆续将水痘疫苗接种纳入常规免疫规划。麻疹、腮腺炎、风疹和水痘联合减毒活疫苗（Measles-Mumps-Rubella-Varicella vaccine，MMRV）联合疫苗的开发基于先前存在的麻腮风三联疫苗（Measles-Mumps-Rubella vaccine，MMR）和 VZV疫苗。自2000年中期以来，有两种MMRV疫苗可用，均已上市，已在美国、澳大利亚、加拿大和许多欧洲国家广泛使用。2005 年 MMRV 联合疫苗在美国获准上市，用于12 月龄至 12 岁儿童，可以替代麻疹-腮腺炎-风疹联合减毒活疫苗（MMR）和单价水痘疫苗。建议在 12~15月龄时接种第一剂疫苗，在 4~6 岁时接种第二剂。接种联合疫苗可以减少免疫接种次数，提高疫苗接种率。既往研究显示，接种MMR后28 d内不能接种水痘疫苗，但是MMRV四价疫苗并未观测到抗原成分之间的互相干扰，而且ProQuad引起的局部反应和全身反应发生率与单价疫苗基本相当，仅发热发生率稍高。Ma等研究表明接种MMRV与麻疹-腮腺炎-风疹疫苗加或不加水痘疫苗（MMR+V/MMR）具有可比的免疫原性和总体安全性。Knuf等［30］表明联合接种2剂MMRV疫苗与单独注射MMR和水痘疫苗一样具有免疫原性和良好的耐受性。此外，Haas对四联疫苗肌肉注射和皮下注射两种不同接种途径的免疫原性及安全性进行了比较，结果显示两组的抗体阳转率均>99%，与肌内注射组相比，皮下注射的红肿和红疹反应率略高，表明两种接种途径的安全性及免疫原性均较好。随着儿童中两剂次水痘疫苗接种策略的实施，针对VZV的免疫应答效果大大提高。对四联疫苗加强免疫后的针对VZV的gpELISA的分析结果显示，两剂次免疫后，超过99%的儿童的抗体浓度可以≥5 U/ml，血清阳转率可以由89%提高至99%，几何平均抗体滴度可以由12 U/ml提高至469 U/ml。两剂次免疫后随访10年观察显示，该接种策略对水痘的预防效果可达到98%，对严重疾病的预防效果可达100%；接受两剂水痘疫苗接种者的突破性水痘发生率比接种1剂者低3.3倍。2.水痘灭活疫苗：水痘灭活疫苗具有安全性高、不良反应发生率低等特点，可解决减毒活疫苗所存在的病毒潜伏性、传染性及毒力回复等问题，因此对于免疫功能低下或缺陷的患者来说，接种灭活疫苗更安全。Sperber等在95位VZV抗体阳性的成年人中研究了减毒活疫苗与灭活疫苗研究的免疫原性与免疫反应特点，结果提示两类疫苗在免疫后6周内诱发的抗体水平无显著性差异。Varis和Vesikari在健康儿童中比较水痘灭活疫苗和水痘减毒活疫苗的疗效，发现两种疫苗都有良好的耐受性，分别有99%和100%检测到血清转换。热灭活的水痘疫苗可能具有更好的安全性，但由于灭活的病毒无法在接受者体内复制，这可能限制了VZV特异性免疫力的提高。目前无上市的水痘灭活疫苗。3.水痘亚单位疫苗：水痘减毒活疫苗作为一种活疫苗，减弱的病毒会潜伏在感觉神经节中，与自然感染的情况类似，在免疫力低下和老年人中会重新激活，产生带状疱疹。作为减活病毒的替代品。理想的人选是一种亚单位疫苗。这种亚单位疫苗可用于针对VZV感染的初级疫苗接种和/或用于增强接种后的免疫反应，以预防带状疱疹。事实上，疫苗病毒已经从接种疫苗后两年内出现的带状疱疹患者中分离出来。Davies等将VZV经细胞培养后，洗涤剂和甲醛处理，蔗糖梯度离心纯化，再用丙酮沉淀，分别制备了含210、240、250和280 μg蛋白的疫苗，该制备工艺保留了VZV蛋白的抗原性和一些特异性糖蛋白的免疫原性，随后的动物实验与人体临床试验均证明疫苗安全有效，没有证据表明兔子或五名人类疫苗接种者有副作用。目前无上市的水痘亚单位疫苗。亚单位疫苗去除了病毒DNA，消除了病毒在接种中出现传播和潜伏感染的危险，比减毒活疫苗更安全。此外，由于亚单位疫苗去除了杂质抗原，降低接种的不良反应，提高了疫苗安全性。但是亚单位疫苗免疫原性较弱，难以激发广泛的免疫应答，特别是T细胞应答偏弱。4.水痘病毒载体疫苗：采用病毒载体的研究策略在理论上可以诱发更有效的免疫反应，因此也有研究者对VZV的病毒载体疫苗进行了研究。Vafai等以痘病毒为载体，将编码病毒特异性糖蛋白gpI（含511个氨基酸残基）的1 642 bp的基因DNA经限制性内切酶切下后克隆到pSCII或pEBI质粒的smaI位点，形成pVVIgpI-51l，与痘苗病毒重组后，获得重组痘苗病毒疫苗VVTgpI-511，感染BSC-1细胞，可以在细胞培养上清液及细胞裂解液中检测到VZV特异蛋白前体产物。另以重组痘苗病毒表达的VVTgpI-511和纯化蛋白TgpI-511分别免疫家兔，检测TgpI-511的抗原性，发现纯化的蛋白TgpI-511可以产生天然VZV的gpI抗体应答，能中和VZV的感染性。上述研究表明，纯化的TgpI-511产物可作为水痘亚单位疫苗的候选物。目前无上市的疫苗，正在研发中。5.水痘核酸疫苗：DNA疫苗具有可同时诱导体液免疫和细胞免疫反应的优势，还可以在宿主体内持久表达，也是基因工程疫苗研究中常用的手段。Hasan等扩增得到VZV病毒糖蛋白E的DNA片段，将其克隆到真核表达质粒pRc/CMV上，构建表达VZV gE的真核表达质粒pRc/CMV-VZV-gE，将重组质粒转化COS7细胞，采用皮下和肌肉注射两种途径免疫8周龄的BALB/c小鼠，结果表明，该疫苗可产生高滴度的中和抗体，其免疫效果具有剂量依赖性，初免200 μg，第四周加强免疫100 μg，可获得持久的免疫。Hasan等进一步研究表明，仅编码分泌型糖蛋白的截短型gE蛋白（gE-D）免疫BALB/c小鼠，可以更好的诱发机体产生IgGl（Th2）。朱塞佩等 构建了gERNA 疫苗。核酸疫苗被称为第三代疫苗，具有很大的应用潜力，但是核酸疫苗作为新的研究方向尚存在许多安全性问题（如自身免疫、超敏反应等），到目前为止尚无核酸疫苗进入临床试验阶段。二带状疱疹疫苗的研究进展带状疱疹临床上尚无特效治疗方法，治疗目标是缓解急性期疼痛，缩短皮损持续时间，防止皮损扩散，预防或减轻带状疱疹后遗神经痛（Postherpetic Neuralgia，PHN）等并发症。治疗方法主要是针对急性带状疱疹的抗病毒治疗和针对相关并发症的其他治疗，但大多仅在带状疱疹急性期使用，且10%~20%伴有较长期PHN的患者，需要数月甚至数年长期使用这些药物来控制疼痛。鉴于带状疱疹和PHN发病率高且治疗费用昂贵，一种有效的预防性疫苗对于降低带状疱疹及其引起的PHN的发病率具有重要的意义。VZV特异性细胞免疫力随着年龄的增长而减退，个体细胞免疫力减弱与体内潜伏病毒再激活的风险增高呈高度正相关。由于水痘与带状疱症均为VZV病毒引起的疾病，Otani等表明儿童期接种水痘疫苗对于预防晚年带状疱疹可能很重要。然而，儿童疫苗接种的有效持续时间尚不清楚，需要进行流行病学研究来检查是否需要加强疫苗接种。Levin等研究表明，使用减毒活疫苗可以提高60岁以上受试者的细胞免疫力。Hayward等与Levin等的非盲研究与Oxman公布的大规模Ⅲ期临床试验结果共同提示，VZV加强免疫是安全的，同时细胞免疫反应的对于预测需要进行VZV加强免疫具有一定的指导意义。Zostavax水痘带状疱疹病毒灭活疫苗是第一个被批准用于预防带状疱疹的疫苗。2006年，美国FDA批准了Zostavax疫苗上市，主要用于60岁以上的老人，可降低那些可能患带状疱疹人群的带状疱疹和PHN的发生率。研究显示 Zostavax 疫苗应用后，60 岁以上成年人带状疱疹的发病率降低 51%；患带状疱疹患者使用后，后遗神经痛的发病率降低 67%；但该疫苗随着接种者年龄的增长，其保护作用会下降，减毒活疫苗在50~59岁人群的保护率为70%，60~69岁的保护率为64%，70岁以上人群的保护率下降至38%。随着时间的延长，Zostavax对预防带状疱疹的效力逐渐降低，观察7~8年的疫苗效果下降至21%~32%，9~11年后与对照组相比效果无统计学差异。Shingrix是一种重组带状疱疹亚单位疫苗，含重组糖蛋白E和AS01B新型复合佐剂［48］。2017年10月25日，美国ACIP推荐 Shingrix 用于年龄≥50岁的成人［52］。2019年5月，Shingrix获批在中国上市［47］，用于≥50 岁成人预防带状疱疹，于2020年6月28日正式在中国市场开售，这也是目前中国唯一已上市的带状疱疹疫苗。研究显示，50岁及以上老年群体接种Shingrix后，感染带状疱疹的风险降低97.2%，接种后第4年为87.9%；对70~79岁人群有90%的保护率，80岁以上为89%。重组带状疱疹疫苗的保护效果、保护持久性均优于减毒活疫苗，因此，美国ACIP推荐50岁及以上免疫正常人群使用以预防带状疱疹及其并发症，既往接种过减毒活疫苗的人可再接种1剂重组带状疱疹疫苗，优先推荐重组疫苗用于预防带状疱疹及其并发症。既往罹患水痘或其他慢性病人群同样被推荐接种重组带状疱疹疫苗。免疫功能低下的个体比免疫功能正常的个体发生带状疱疹及相关并发症的风险更大。Shingrix是第一个被批准用于免疫功能低下人群的带状疱疹疫苗。2021年7月，美国FDA批准Shingrix扩大适用人群：用于18岁及以上免疫功能低下的成人，预防带状疱疹。适用于由于免疫缺陷、或由已知疾病或治疗导致免疫抑制、有或将有增加的带状疱疹风险的18岁及以上成人。结语与展望疫苗通常是预防传染病最经济有效的手段，随着其他疫苗可预防疾病得到有效控制，水痘及带状疱疹会逐渐成为受关注的公共卫生问题。VZV呈全球流行，每年全球会出现大量水痘及带状疱疹病例，VZV会造成不可估量的疾病负担和社会成本。Lin等研究发现三分之一的带状疱疹病例发生在40岁以下的人群中，三分之一发生在40~60岁的人群中以及三分之一出现在60岁以上的人群中。水痘疫苗在降低全球该疾病的发病率和负担方面非常有效。作为疫苗可预防疾病，水痘及带状疱疹均已研发出安全有效的疫苗。水痘疫苗在国内外已被大量使用，带状疱疹疫苗也于2020年在国内上市，可通过提高接种率发挥疫苗的群体保护效果。文献中有强有力的证据表明，水痘疫苗在预防与该疾病相关的发病率和死亡率方面是安全有效的。然而，尽管疫苗有效性令人印象深刻，并非所有国家都建议常规接种水痘疫苗，不同国家、不同社会人口学背景对接种水痘疫苗的知识和态度存在较大差异，包括疫苗接种费用以及父母对待疫苗的态度或国家是否报销儿童疫苗接种费用等。事实上，此建议目前仅存在于 33 个国家/地区。然而，在实施的地方，真实世界的数据显示，与疫苗接种前的时期相比，水痘发病率显著降低。在单剂方案之后，发病率减少高达 74%，在两剂方案之后，观察到减少超过 90%，疫苗接种计划也与水痘相关住院率和死亡率的降低有关。目前的水痘疫苗均为减毒活疫苗，可能发生潜伏感染。与此同时，与疫苗本身及预防接种相关的技术问题也需亟待完善。监测水痘疫苗大量使用后（尤其是水痘疫苗纳入免疫规划）的水痘和带状疱疹发病情况以及研发联合疫苗的安全性，在 10~24月龄的儿童中首次接种 MMRV 疫苗与癫痫发作或热性惊厥的风险升高有关，需要基于更严格的研究设计开展进一步的上市后重新研究，以确认研究结果。因此，探索更加安全有效、不含病毒核酸的疫苗仍是值得深入的研究方向。作者：陶静波；万斌斌；陈劲华；贾建伟；成航；楼灵巧；骆淑英.中华预防医学杂志, 2023,57(2) :286-292. DOI: 10.3760/cma.j.cn112150-20220829-00853