The 11th edition of Harrison's Principles of Internal Medicine welcomes Anthony Fauci to its editorial staff, in addition to more than 85 new contributors. While the organization of the book is similar to previous editions, major emphasis has been placed on disorders that affect multiple organ systems. Important advances in genetics, immunology, and oncology are emphasized. Many chapters of the book have been rewritten and describe major advances in internal medicine. Subjects that received only a paragraph or two of attention in previous editions are now covered in entire chapters. Among the chapters that have been extensively revised are the chapters on infections in the compromised host, on skin rashes in infections, on many of the viral infections, including cytomegalovirus and Epstein-Barr virus, on sexually transmitted diseases, on diabetes mellitus, on disorders of bone and mineral metabolism, and on lymphadenopathy and splenomegaly. The major revisions in these chapters and many

Harrison's Principles of Internal Medicine

This report updates the 2020-21 recommendations of the Advisory Committee on Immunization Practices (ACIP) regarding the use of seasonal influenza vaccines in the United States (MMWR Recomm Rep 2020;69[No. RR-8]). Routine annual influenza vaccination is recommended for all persons aged ≥6 months who do not have contraindications. For each recipient, a licensed and age-appropriate vaccine should be used. ACIP makes no preferential recommendation for a specific vaccine when more than one licensed, recommended, and age-appropriate vaccine is available. During the 2021-22 influenza season, the following types of vaccines are expected to be available: inactivated influenza vaccines (IIV4s), recombinant influenza vaccine (RIV4), and live attenuated influenza vaccine (LAIV4).The 2021-22 influenza season is expected to coincide with continued circulation of SARS-CoV-2, the virus that causes COVID-19. Influenza vaccination of persons aged ≥6 months to reduce prevalence of illness caused by influenza will reduce symptoms that might be confused with those of COVID-19. Prevention of and reduction in the severity of influenza illness and reduction of outpatient visits, hospitalizations, and intensive care unit admissions through influenza vaccination also could alleviate stress on the U.S. health care system. Guidance for vaccine planning during the pandemic is available at https://www.cdc.gov/vaccines/pandemic-guidance/index.html. Recommendations for the use of COVID-19 vaccines are available at https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/covid-19.html, and additional clinical guidance is available at https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html.Updates described in this report reflect discussions during public meetings of ACIP that were held on October 28, 2020; February 25, 2021; and June 24, 2021. Primary updates to this report include the following six items. First, all seasonal influenza vaccines available in the United States for the 2021-22 season are expected to be quadrivalent. Second, the composition of 2021-22 U.S. influenza vaccines includes updates to the influenza A(H1N1)pdm09 and influenza A(H3N2) components. U.S.-licensed influenza vaccines will contain hemagglutinin derived from an influenza A/Victoria/2570/2019 (H1N1)pdm09-like virus (for egg-based vaccines) or an influenza A/Wisconsin/588/2019 (H1N1)pdm09-like virus (for cell culture-based and recombinant vaccines), an influenza A/Cambodia/e0826360/2020 (H3N2)-like virus, an influenza B/Washington/02/2019 (Victoria lineage)-like virus, and an influenza B/Phuket/3073/2013 (Yamagata lineage)-like virus. Third, the approved age indication for the cell culture-based inactivated influenza vaccine, Flucelvax Quadrivalent (ccIIV4), has been expanded from ages ≥4 years to ages ≥2 years. Fourth, discussion of administration of influenza vaccines with other vaccines includes considerations for coadministration of influenza vaccines and COVID-19 vaccines. Providers should also consult current ACIP COVID-19 vaccine recommendations and CDC guidance concerning coadministration of these vaccines with influenza vaccines. Vaccines that are given at the same time should be administered in separate anatomic sites. Fifth, guidance concerning timing of influenza vaccination now states that vaccination soon after vaccine becomes available can be considered for pregnant women in the third trimester. As previously recommended, children who need 2 doses (children aged 6 months through 8 years who have never received influenza vaccine or who have not previously received a lifetime total of ≥2 doses) should receive their first dose as soon as possible after vaccine becomes available to allow the second dose (which must be administered ≥4 weeks later) to be received by the end of October. For nonpregnant adults, vaccination in July and August should be avoided unless there is concern that later vaccination might not be possible. Sixth, contraindications and precautions to the use of ccIIV4 and RIV4 have been modified, specifically with regard to persons with a history of severe allergic reaction (e.g., anaphylaxis) to an influenza vaccine. A history of a severe allergic reaction to a previous dose of any egg-based IIV, LAIV, or RIV of any valency is a precaution to use of ccIIV4. A history of a severe allergic reaction to a previous dose of any egg-based IIV, ccIIV, or LAIV of any valency is a precaution to use of RIV4. Use of ccIIV4 and RIV4 in such instances should occur in an inpatient or outpatient medical setting under supervision of a provider who can recognize and manage a severe allergic reaction; providers can also consider consulting with an allergist to help identify the vaccine component responsible for the reaction. For ccIIV4, history of a severe allergic reaction (e.g., anaphylaxis) to any ccIIV of any valency or any component of ccIIV4 is a contraindication to future use of ccIIV4. For RIV4, history of a severe allergic reaction (e.g., anaphylaxis) to any RIV of any valency or any component of RIV4 is a contraindication to future use of RIV4. This report focuses on recommendations for the use of vaccines for the prevention and control of seasonal influenza during the 2021-22 influenza season in the United States. A brief summary of the recommendations and a link to the most recent Background Document containing additional information are available at https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/flu.html. These recommendations apply to U.S.-licensed influenza vaccines used according to Food and Drug Administration-licensed indications. Updates and other information are available from CDC's influenza website (https://www.cdc.gov/flu); vaccination and health care providers should check this site periodically for additional information.

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Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices - United States, 2020-21 Influenza Season.

Summary Background 18 500 laboratory-confirmed deaths caused by the 2009 pandemic influenza A H1N1 were reported worldwide for the period April, 2009, to August, 2010. This number is likely to be only a fraction of the true number of the deaths associated with 2009 pandemic influenza A H1N1. We aimed to estimate the global number of deaths during the first 12 months of virus circulation in each country. Methods We calculated crude respiratory mortality rates associated with the 2009 pandemic influenza A H1N1 strain by age (0–17 years, 18–64 years, and >64 years) using the cumulative (12 months) virus-associated symptomatic attack rates from 12 countries and symptomatic case fatality ratios (sCFR) from five high-income countries. To adjust crude mortality rates for differences between countries in risk of death from influenza, we developed a respiratory mortality multiplier equal to the ratio of the median lower respiratory tract infection mortality rate in each WHO region mortality stratum to the median in countries with very low mortality. We calculated cardiovascular disease mortality rates associated with 2009 pandemic influenza A H1N1 infection with the ratio of excess deaths from cardiovascular and respiratory diseases during the pandemic in five countries and multiplied these values by the crude respiratory disease mortality rate associated with the virus. Respiratory and cardiovascular mortality rates associated with 2009 pandemic influenza A H1N1 were multiplied by age to calculate the number of associated deaths. Findings We estimate that globally there were 201 200 respiratory deaths (range 105 700–395 600) with an additional 83 300 cardiovascular deaths (46 000–179 900) associated with 2009 pandemic influenza A H1N1. 80% of the respiratory and cardiovascular deaths were in people younger than 65 years and 51% occurred in southeast Asia and Africa. Interpretation Our estimate of respiratory and cardiovascular mortality associated with the 2009 pandemic influenza A H1N1 was 15 times higher than reported laboratory-confirmed deaths. Although no estimates of sCFRs were available from Africa and southeast Asia, a disproportionate number of estimated pandemic deaths might have occurred in these regions. Therefore, efforts to prevent influenza need to effectively target these regions in future pandemics. Funding None.

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Estimated global mortality associated with the first 12 months of 2009 pandemic influenza A H1N1 virus circulation: a modelling study

Vaccines containing novel adjuvant formulations are increasingly reaching advanced development and licensing stages, providing new tools to fill previously unmet clinical needs. However, many adjuvants fail during product development owing to factors such as manufacturability, stability, lack of effectiveness, unacceptable levels of tolerability or safety concerns. This Review outlines the potential benefits of adjuvants in current and future vaccines and describes the importance of formulation and mechanisms of action of adjuvants. Moreover, we emphasize safety considerations and other crucial aspects in the clinical development of effective adjuvants that will help facilitate effective next-generation vaccines against devastating infectious diseases.

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Key roles of adjuvants in modern vaccines

SARS-CoV-2 Vaccines: Status Report.

OBJECTIVE: To update the estimated global incidence of Japanese encephalitis (JE) using recent data for the purpose of guiding prevention and control efforts. METHODS: Thirty-two areas endemic for JE in 24 Asian and Western Pacific countries were sorted into 10 incidence groups on the basis of published data and expert opinion. Population-based surveillance studies using laboratory-confirmed cases were sought for each incidence group by a computerized search of the scientific literature. When no eligible studies existed for a particular incidence group, incidence data were extrapolated from related groups. FINDINGS: A total of 12 eligible studies representing 7 of 10 incidence groups in 24 JE-endemic countries were identified.Approximately 67 900 JE cases typically occur annually (overall incidence: 1.8 per 100 000), of which only about 10% are reported to the World Health Organization. Approximately 33 900 (50%) of these cases occur in China (excluding Taiwan) and approximately 51 000 (75%) occur in children aged 0-14 years (incidence: 5.4 per 100 000). Approximately 55 000 (81%) cases occur in areas with well established or developing JE vaccination programmes, while approximately 12 900 (19%) occur in areas with minimal or no JE vaccination programmes. CONCLUSION: Recent data allowed us to refine the estimate of the global incidence of JE, which remains substantial despite improvements in vaccination coverage. More and better incidence studies in selected countries, particularly China and India, are needed to further refine these estimates.

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Estimated global incidence of Japanese encephalitis: a systematic review

MF59 is a well-established, safe and potent vaccine adjuvant that has been licensed for more than 13 years for use in an influenza vaccine focused on elderly subjects (Fluad®), Novartis, Cambridge, MA, USA). Recently, MF59 was shown to be safe in a seasonal influenza vaccine for young children and was able to increase vaccine efficacy from 43 to 89%. A key and consistent feature of MF59 is the ability of the emulsion to induce fast priming of influenza antigen-specific CD4(+) T-cell responses, to induce strong and long-lasting memory T- and B-cell responses and to broaden the immune response beyond the influenza strains actually included in the vaccine. The enhanced breadth of response is valuable in the seasonal setting, but is particularly valuable in a (pre-) pandemic setting, when it is difficult to predict which strain will emerge to cause the pandemic. We have shown that the ability of MF59 to increase the breadth of immune response against influenza vaccines is mainly due to the spreading of the repertoire of the B-cell epitopes recognized on the hemagglutinin and neuraminidase of the influenza virus.

MF59 adjuvant: the best insurance against influenza strain diversity.

Background: A potential association between the new onset of narcolepsy accompanied by cataplexy – a putative autoimmune disorder, and vaccination with an AS03-adjuvanted A(H1N1) pandemic influenza vaccine is under investigation. We sought cases of narcolepsy from the pharmacovigilance database of a pandemic vaccine adjuvanted with another emulsion adjuvant, MF59®, and a pooled clinical trials database of MF59-adjuvanted and non-adjuvanted influenza vaccine recipients. Methods: Using 6 narrowly restrictive and 24 broad sleep disturbance-related MedDRA preferred search terms (PT), we analysed spontaneous adverse events (AEs) reports received through July 31, 2010 and adjudicated suspected cases with onset 1 week–3 months after vaccination, against standardized clinical criteria defining narcolepsy. A pooled clinical trials database of 115 trials comprising 79,004 subjects receiving various MF59-adjuvanted and non-adjuvanted influenza vaccines in controlled and uncontrolled trials was analysed for c...

Explorations of clinical trials and pharmacovigilance databases of MF59®-adjuvanted influenza vaccines for associated cases of narcolepsy.

Vaccines of the invention include at least four influenza virus strains. In some embodiments, the vaccines are produced in cell culture rather than in eggs. In some embodiments, the vaccines include an adjuvant. In some embodiments, the vaccines are not split or whole virion vaccines, but are live or purified glycoprotein vaccines. In some embodiments, the vaccines contain substantially the same mass of hemagglutinin (HA) for each of the influenza virus strains. In some embodiments, the four strains will include two influenza A virus strains and two influenza B virus strains ('A-A-B-B'). In other embodiments, the four strains will include three influenza A virus strains and one influenza B virus strain ('A-A-A-B').

Vaccines including antigen from four strains of influenza virus

Influenza directly or indirectly contributes to the four leading causes of global mortality, at rates that are highest in older adults. As the proportion of older adults in the Korean population is greater than in most other countries, influenza prevention is a greater public health priority in Korea than elsewhere. Conventional inactivated influenza vaccine (IIV) is less immunogenic and efficacious (-50%) in older than in young adults, but adjuvanting the vaccine with oil-in-water emulsion MF59® increases immunogenicity, resulting in comparatively higher levels of hemagglutination inhibition antibodies and greater protection against all influenza, as well as cases requiring hospitalization. A recent observational study demonstrated that the adjuvanted vaccine protected older adults against influenza in a year when nonadjuvanted IIV was ineffective. In another multiyear study, the adjuvanted vaccine was estimated to be 25% more effective in preventing pneumonia and influenza hospitalizations compared to nonadjuvanted vaccine. Although MF59-adjuvanted vaccine is transiently more reactogenic than nonadjuvanted vaccine, there is no evidence that it increases risks for serious adverse events, including those with an autoimmune etiology. Experience thus far indicates a favorable balance of benefit to risk for MF59. This may reflect the adjuvant's mechanism of action in which the squalene oil emulsion increases antibody responses to co-administered antigen without acting more generally as an immunopotentiator.

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Theodore F. Tsai

Papers

Estimated global incidence of Japanese encephalitis: a systematic review

MF59 adjuvant: the best insurance against influenza strain diversity.

Explorations of clinical trials and pharmacovigilance databases of MF59®-adjuvanted influenza vaccines for associated cases of narcolepsy.

Vaccines including antigen from four strains of influenza virus

Fluad®-MF59®-Adjuvanted Influenza Vaccine in Older Adults