key: cord-0773945-m1hlni1w
authors: Neuzil, Kathleen M
title: Prevention and Control of Coronavirus Disease 2019: Where Do We Go From Here?
date: 2022-02-03
journal: Clin Infect Dis
DOI: 10.1093/cid/ciac090
sha: f49afee39fdfa7919bb09e76986554ff729cdd01
doc_id: 773945
cord_uid: m1hlni1w

nan

Respiratory viruses have plagued humanity for millennia. The latest respiratory virus to emerge-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-has caused the pandemic of our lifetimes. The social, economic, and health consequences have been staggering, and the end is not yet in sight. Historic vaccine development efforts with rapid rollout of highly effective vaccines in the United States and elsewhere have prevented millions of cases and saved hundreds of thousands of lives [1] . Yet, more than a year after emergency use authorization of coronavirus disease 2019 (COVID-19) vaccines, almost half of the global population remains unvaccinated, and <10% of people in low-income countries have received a single dose of vaccine [2] . These large unvaccinated populations, and vaccinated populations with poor vaccine responses, remain at high risk for serious outcomes and death due to COVID-19 [3] .

Two new manuscripts in Clinical Infectious Diseases provide additional data to inform pandemic strategy, and highlight that vaccines are working extremely well to prevent medically significant illness. The first manuscript, from Denmark, prospectively followed a population of >1 million individuals vaccinated with the Pfizer-BioNTech messenger RNA (mRNA) vaccine [4] . Polymerase chain reaction testing for SARS-CoV-2 infection was free and widely available, and test results were captured in national registries. While the authors found that the overall risk of breakthrough infection was low, breakthrough infections did increase over time during the 8-month follow-up period ending in September 2021. The second manuscript, from Japan [5] , evaluated breakthrough infections in a cohort of >2400 medical center staff who received 2 doses of Pfizer-BioNTech mRNA vaccine between March and June 2021. Prospective follow-up of the cohort included periodic serologic and nasal sampling through well-established infection control protocols. During the wave of Delta variant infection, 17 cases of breakthrough infection were identified, all of which were mild or asymptomatic. After matching vaccinated breakthrough cases to vaccinated controls without breakthrough infection, the authors found no difference in postvaccination neutralizing antibodies against the wildtype virus, Alpha variant, or Delta variant between the 2 groups.

The findings in the second study are at odds with several analyses utilizing data from the randomized, controlled clinical trials demonstrating that both binding and pseudoneutralization antibodies after the second mRNA vaccine correlated with vaccine efficacy [6] . Possible reasons for these discrepancies include residual unmeasured confounding in the observational study (eg, those with breakthrough infections were at higher or more frequent risk of exposure or had medical conditions that would lead to more rapid waning of postvaccination antibody); differences in the SARS-CoV-2 circulating strain (vaccine strain in the initial trial results, and Delta variant in the observational study); or differences in the measured outcomes (predefined symptomatic disease in the trials vs asymptomatic or mild disease in the observational study). Although the antibody assays employed were different between the observational study and the clinical trials, the relative relationships of the antibody to the outcome should remain valid. Alternatively, the similar antibody responses found among those with and without breakthrough infection in this study may indicate that protection against the heterologous Delta infections may be mediated by immune markers such as mucosal antibodies or functional T cells that were not measured as part of the study.

Importantly, both studies were done in periods before the emergence of the Omicron variant. The historic numbers of infections seen with Omicron are attributed to its transmission efficiency and immune escape capabilities. In most studies, binding and neutralization antibody titers elicited by current vaccines to Omicron are lower than titers against the ancestral, Alpha, and Delta variants, and increase after administration of a booster dose [7] . Vaccine effectiveness for Omicron infections is lower and less durable when compared to Delta infections, although effectiveness is better preserved against severe disease and is enhanced by a booster dose, at least for a limited period of time [8, 9] .

Preventing any infection with SARS-CoV-2, even in healthy populations with robust immune responses, seems unlikely with our current tools given the ease with which the virus spreads and its ability to rapidly mutate to its advantage. The primary goal of our current vaccination efforts must remain the prevention of serious disease and death, not the prevention of asymptomatic or mildly symptomatic infections [10] . This is not to suggest that nonserious disease occurs without consequences. Importantly, the vaccinated may retain the ability to transmit virus to the unvaccinated. While virus detected in the nose does not equal virus being transmitted, the concern for the latter increases as the quantity and duration of virus detection in the upper respiratory tract increase. Furthermore, the impact on societal functioning remains if hospitals and emergency rooms are full and healthcare workers, school teachers, and other essential personnel are infected and restricted from their work activities. While the world is tiring of this pandemic, these are compelling reasons to continue mask wearing, social distancing, and frequent testing.

So what can be done? Well, first and foremost, efforts must continue to vaccinate as many people as possible as quickly as possible, on a global scale. Unmitigated global replication of this virus will continue to drive the emergence of new variants, as evidenced by the emergence of the Delta and Omicron variants. Eliminating viral replication in the nose is a difficult goal that is unlikely to be achieved solely by vaccines designed to elicit systemic antibodies. Our experiences with influenza have taught us that repeatedly over the decades. Research and development on alternative vaccines and vaccination schedules that may result in broader and more durable immunity, including mucosal and cell-mediated immunity, should continue, recognizing this is a long-term investment and not a short-term expectation. Likewise, understanding the degree to which exposure to circulating virus provides a boost to our vaccine-induced immunity must be understood. While manufacturing and testing new single or multivariant vaccines is essential to better understand immune responses, the goal must be broad immunity and not simply strain-specific immunity. Chasing strain changes for a global vaccination program is fraught with challenges-another lesson we have learned from influenza.

Recognizing that vaccination alone is insufficient to control this pandemic, an integrated strategy that optimizes the use of all available resources is preferrable. This includes monoclonal antibodies with broad activity against all variants for treatment as well as prophylaxis, particularly for the immunocompromised or institutional outbreak situations. Likewise, a greater supply and breadth of antivirals, and the testing of antiviral combinations, must be pursued as an adjunct to vaccination. From the public health standpoint, we have shown the great value of social distancing and wearing masks to prevent not only SARS-CoV-2, but also other respiratory viruses that hospitalize and sicken infants, the elderly, and vulnerable populations every year [11] . As social distancing and mask restrictions have been loosened, many respiratory viruses have returned; babies are again being hospitalized with respiratory syncytial virus (RSV), and adults are being infected as well. While the appetite for universal and permanent masking is understandably low, are there situations for which wearing a mask might become the norm, even after the COVID-19 pandemic subsides? For example, should masks be considered for all visitors to nursing homes during the winter respiratory season, or when visiting an infant? Certainly the paradigm for not going to work or school when sick should continue after the pandemic ends, accompanied by liberal leave policy for such circumstances. Perhaps rapid multipathogen, point-of-care respiratory virus tests will become the norm, allowing us to change our behavior if we have influenza, RSV, or COVID-19. Ventilation can and should be improved in schools, healthcare centers, restaurants, theaters, and other buildings where large numbers of people gather.

The time is now to vaccinate the world's people and to acknowledge that SARS-CoV-2 will continue to circulate and evolve. It is highly likely that we will need to live with the virus in coexistence, being protected from severe disease by vaccination and being boosted with vaccines and by exposure to circulating virus under the cover of vaccines. Intellectual property must be shared and global manufacturing capacity must be strengthened to further enhance equity of vaccine supply and distribution since it is likely that global vaccination efforts will need to continue beyond the initial effort. With a global vision, cooperation, and resources, we can ensure that scientific and public health advances realized during this terrible pandemic will benefit us now and prepare us for the future.

Potential conflicts of interest. The author was an investigator and her institution received funding for the phase 1 trial of the Pfizer-BioNTech COVID-19 mRNA vaccine. The author received no salary support. The author has received salary support from the National Institutes of Health for her role in the design and execution of the COVID-19 trials funded as part of the COVID-19 Prevention Network.

The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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