COVID-19: Epidemiology, virology, and prevention

INTRODUCTION — 

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 in Wuhan, a city in Hubei Province of China, and subsequently spread worldwide, causing a major global pandemic. Prior to the emergence of SARS-CoV-2, coronaviruses were well known infectious agents in many species, including humans. Four common cold coronaviruses (HCoV-229E, HCoV-HKU1, HCoV-NL63, and HCoV-OC43) were estimated to cause 15 to 30 percent of mild upper respiratory infections, with significant seasonal variation [1,2]. Two other pathogenic coronaviruses had previously caused severe disease in humans: severe acute respiratory syndrome coronavirus (SARS-CoV), which circulated from 2002 to 2004 following a spillover event from an animal host [3], and Middle East Respiratory Syndrome (MERS), which emerged in 2012 and causes ongoing infection associated with repeated spillover events from camel reservoirs and occasional clusters of human-to-human transmission [4,5].

Before the World Health Organization (WHO) declared an end to the coronavirus disease 2019 (COVID-19) global health emergency in May 2023, SARS-CoV-2 infection resulted in an estimated 15 million excess deaths in 2020 and 2021 alone [6]. As SARS-CoV-2 transitions to endemicity, it remains an important cause of illness around the world.

This topic will discuss the virology, epidemiology, and prevention of COVID-19. The clinical features and diagnosis of COVID-19 are discussed in detail elsewhere. (See "COVID-19: Clinical features" and "COVID-19: Diagnosis".)

The management of COVID-19 is also discussed in detail elsewhere:

●(See "COVID-19: Management in hospitalized adults".)

●(See "COVID-19: Evaluation and management of adults with acute infection in the outpatient setting".)

●(See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection".)

Issues related to COVID-19 in pregnant women and children are discussed elsewhere:

●(See "COVID-19: Overview of pregnancy issues".)

●(See "COVID-19: Clinical manifestations and diagnosis in children" and "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis".)

See specific topic reviews for details on complications of COVID-19 and issues related to COVID-19 in other patient populations.

VIROLOGY AND IMMUNOLOGY

Coronavirus virology — Coronaviruses are enveloped positive-sensed, single-stranded RNA viruses. SARS-CoV-2 is a betacoronavirus. It is in the same subgenus as, but is in a different clade from, the severe acute respiratory syndrome (SARS) virus. The Middle East Respiratory Syndrome (MERS) virus is a more distantly related betacoronavirus [7,8]. The closest RNA sequence similarities to SARS-CoV-2 are found in coronaviruses isolated from bats, which were the likely animal reservoir prior to spillover to humans [9,10]. Pangolins are a possible intermediate host for SARS-CoV-2 prior to passage to humans.

The virology of coronaviruses is discussed in detail elsewhere. (See "Common cold coronaviruses", section on 'Coronavirus virology'.)

SARS-CoV-2 cell entry and key proteins — The primary host cell entry receptor for SARS-CoV-2 is the same as for SARS-CoV, the angiotensin-converting enzyme 2 (ACE2) [11]. SARS-CoV-2 binds to ACE2 through the receptor-binding domain of its spike protein (figure 1).

Additional enzymatic interactions between SARS-CoV-2 and host cells determine specific cell tropism, which has evolved with the virus. Specifically, following ACE2 binding, the original SARS-CoV-2 virus and some subsequent variants, including Delta, enter cells after a host protease (most often the TMPRSS2 enzyme) cleaves the spike protein, enabling subsequent membrane fusion and cell entry [12,13]. Since TMPRSS2 is expressed at high levels in lung epithelial cells, these variants replicated efficiently in the lungs. Omicron-lineage variants, in contrast, mostly enter host cells through a different pathway involving cathepsin-dependent endocytosis and use the TMPRSS2-mediated pathway far less efficiently [14]. Thus, Omicron-lineage variants replicate more efficiently in the upper airways, where TMPRSS2 expression is lower than in the lungs [15]. (See 'Viral evolution and variants of concern' below.)

SARS-CoV-2 antivirals have targeted one of two important viral proteins:

●RNA-dependent RNA polymerase (RdRp) – This is an error-prone enzyme responsible for viral replication [16]. Remdesivir, molnupiravir, and mindeudesivir (a drug available in China) target the RdRp.

●3CL protease – This is also called the main protease, and it cleaves the polyproteins encoded by the SARS-CoV-2 RNA. Ritonavir-boosted nirmatrelvir [17], ritonavir-boosted simnotrelvir, and ensitrelvir target this protease.

Viral evolution and variants of concern

SARS-CoV-2 evolution and nomenclature

●Mechanisms of evolution – SARS-CoV-2, like many other RNA viruses, has evolved over time through random mutations from replication infidelity, although its intrinsic mutation rate is lower than many other RNA viruses (including HIV and HCV) because of a proofreading mechanism [18].

Recombination is another mechanism for evolution. This occurs when a host is simultaneously infected with two distinct SARS-CoV-2 viruses, and a progeny virus emerges that includes RNA sequences from both [19].

Rapid accumulation of many mutations may occur in highly immunocompromised individuals with persistent or chronic SARS-CoV-2 infections [18,20,21]. (See 'Viral shedding and period of infectiousness' below.)

Detailed study of the various SARS-CoV-2 viruses and variants of concern has illustrated important features of the nature of viral evolution as well as the impact of different viruses on the hosts. Most importantly, selective advantage to a progeny virus mainly comes from intrinsic viral factors (often leading to replication advantage) or from greater evasion of the host immune response (most commonly from antigenic shift).

●Variant nomenclature – Although most mutations in the SARS-CoV-2 genome have no impact on viral function, some convey a selective advantage to the progeny virus, which thus accumulates as a detectable variant at a population level. The World Health Organization (WHO) has designated labels for notable variants based on the Greek alphabet [22]. Each variant also has several designations based on the nomenclature used by distinct phylogenetic classification systems. The Pango dynamic nomenclature is a commonly referenced and important system, in which each major lineage begins with a letter, followed by additional letters or numbers (eg, B.1.1.529 or BA.1 are the Pango delineations of the original Omicron virus); recombinant viruses include an “X” in their Pango nomenclature [23,24]. Some SARS-CoV-2 mutated viruses have been designated variants of concern because of increased transmissibility, associated disease severity, or immune evasion. (See 'Pre-Omicron SARS-CoV-2 viruses' below and 'Omicron (B.1.1.529) and its sublineages' below.)

●Mutations associated with intrinsic replication advantage – Since the emergence of SARS-CoV-2, several mutations have been shown to convey an intrinsic replication advantage independent of immune escape mechanisms:

•The D614G spike mutation enhances binding of the virus with the host cell ACE2 receptor, leading to a 20 percent increase in transmissibility [25].

•The N501Y substitution also conveys an inherent replication advantage over wild-type viruses [26]. This substitution is associated in increased affinity between the spike protein and ACE2; virus containing this mutation achieves a higher effective viral load.

Pre-Omicron SARS-CoV-2 viruses — Until around September 2020, there was remarkable stability among SARS-CoV-2 virus genomes, as the population was essentially fully susceptible and there was little selective pressure from population-level immunity to drive viral evolution. Subsequently, a series of variants emerged that became globally or regionally dominant, displacing prior SARS-CoV-2 viruses, with mutational profiles that conveyed increased intrinsic transmissibility, immune evasiveness, or both:

●The Alpha variant (B.1.1.7 lineage) was approximately 50 to 75 percent more transmissible than prior SARS-CoV-2 viruses and became globally dominant in late 2020 until the emergence of the Delta variant [27-33]. Compared with the original, wild-type virus, Alpha had 19 mutations across the viral genome, including 8 substitutions or deletions in the spike protein [26]. These included D614G and N501Y, as well as deletion of codons 69 and 70, which conveyed inherent replication advantage over wild-type virus. (See 'SARS-CoV-2 evolution and nomenclature' above.)

●The Beta (B.1.351 lineage) and Gamma (P.1 lineage) variants became regionally dominant in late 2020 in South Africa and Brazil, respectively, but were not globally dominant [34,35]. Beta was notable for its immune evasion; convalescent and post-vaccination plasma did not neutralize viral constructs with Beta spike protein as well as those with wild-type spike protein [36-39]. Gamma included the same N501Y mutation found in Alpha as well as additional spike mutations associated with increased transmissibility [40]. It also evaded immune response to prior SARS-CoV-2 viruses.

●Delta emerged in December 2020, became dominant worldwide in mid-2021, and remained so until emergence of the Omicron variant [41,42]. Delta was more transmissible than any of the prior variants.

Omicron (B.1.1.529) and its sublineages — The Omicron variant, with around 50 novel mutations compared with wild-type virus, including 34 in the spike gene, was first reported from Botswana and very soon thereafter from South Africa in November 2021 [43]. It rapidly spread around the globe, replacing all previously dominant circulating SARS-CoV-2 viruses. Subsequently, Omicron sublineages have repeatedly emerged and replaced the previous predominant sublineage; each prevailing sublineage has some advantage over the prior one, whether it is increased intrinsic transmissibility or increased evasion of existing immune responses or both (table 1).

In the United States, the proportion of Omicron sublineages circulating in different regions of the country can be found on the Centers for Disease Control and Prevention (CDC) variant tracker website.

Omicron sublineages have a number of features that distinguish them from previously circulating variants:

●Increased transmissibility – Omicron sublineages are more transmissible compared with prior SARS-CoV-2 variants. Intrinsic transmissibility of a virus can be estimated by the basic reproductive number (R0), which is the number of secondary cases caused by each index case among a fully susceptible population. The R0 for SARS-CoV-2 increased from 2.5 for the original virus [44] to around 5 for Delta [45] and to greater than 8 for Omicron [46].

Accordingly, Omicron (specifically the BA.1 sublineage) had been associated with a higher secondary attack rate compared with Delta (in one study, 25 versus 19 percent) [47]. Another study of household contacts of patients with Omicron BA.1 infection suggested a secondary attack rate of 53 percent, which varied by vaccination status of the index patient and use of preventive measures in the household [48]. Data on secondary attack rates of other Omicron sublineages are lacking. Furthermore, secondary attack rates relative to the intrinsic transmissibility of a variant have declined as more individuals have developed immunity from vaccination and/or prior infection.

The tropism of the BA.1 virus for the nasopharynx may have contributed to increased transmissibility compared with prior SARS-CoV-2 viruses, since it could more readily establish an infection in the more accessible nasopharynx and upper airways [18]. (See 'SARS-CoV-2 cell entry and key proteins' above.)

●Immune evasion – Omicron more effectively evades pre-existing immunity than prior SARS-CoV-2 viruses [49,50]. In a case-control study from Qatar, a history of prior infection was associated with an 85 to 90 percent lower risk of infection with Alpha, Delta, or Beta variants, but only a 56 percent lower risk with Omicron BA.1 [50]. (See 'Risk of reinfection' below.)

•Escape from humoral immunity – The best confirmatory data for escape from humoral immunity comes from laboratory studies showing that sera from individuals with prior infection or prior vaccination did not neutralize Omicron as well as earlier variants; in some cases, neutralizing activity against Omicron was undetectable in convalescent as well as post-vaccination sera [51-53]. Similarly, compared with Omicron BA.1, sublineages BA.4 and BA.5 were not as well recognized by antibodies elicited by BA.1 or BA.2 infection or vaccination [54-56]. However, prior infection with one Omicron subvariant may still provide some protection against subsequent infection with certain other subvariants, even if in vitro studies suggest low antibody cross-reactivity [57-59]. As an example, the risk of reinfection with BA.4 and BA.5 was lower following BA.1 or BA.2 infection than following infection with a pre-Omicron variant [57,58]. The impact of vaccine-induced immunity on risk of Omicron infection is discussed elsewhere. (See "COVID-19: Vaccines", section on 'Benefits of vaccination'.)

Omicron sublineages have also escaped neutralization by monoclonal antibodies derived from individuals infected with prior SARS-CoV-2 viruses, thus limiting the preventive and therapeutic benefits of such interventions. (See 'Limited role for monoclonal antibodies in selected patients' below.)

•Less impact on cellular immunity – T-cell immunity against different SARS CoV-2 variants, including Omicron, is more preserved, likely explaining protection against severe outcomes for individuals with prior infection and/or vaccination [60]. Unlike antibody responses, which are focused on immunodominant regions of the viral spike protein that are prone to escape from humoral immunity, T-cell responses after infection and vaccination are broad and directed against conserved viral epitopes. However, cross-variant T-cell responses may be attenuated in the setting of certain immunocompromising conditions [61].

•Evasion of innate immune responses – This is another important mechanism for SARS-CoV-2 immunopathogenesis. For example, the Omicron subvariants BA.4 and BA.5 had higher levels of Orf6 gene expression leading to antagonism of host innate immunity [62].

●Symptom profile – Symptomatic infection is most commonly associated with respiratory tract symptoms, regardless of the infecting SARS-CoV-2 variant. However, certain symptoms may have been more prominent with specific variants, in part because of different tropism. As an example, sore throat has been more prevalent with Omicron sublineage infections, while loss of smell or taste was more prevalent with Delta and pre-Delta infections [63]. The clinical features of SARS-CoV-2 infection are discussed in detail elsewhere. (See "COVID-19: Clinical features", section on 'Clinical manifestations'.)

●Disease severity – Observational data from multiple studies suggest that the risk of severe disease or death with Omicron infection is lower than with prior variants of concern [64-73]. An analysis from England estimated that the risk of hospital admission or death with Omicron was approximately one-third that with Delta, adjusted for age, sex, vaccination status, and prior infection [67].

The reduced risk for severe disease may reflect partial protection conferred by prior infection or vaccination. However, animal studies show lower viral levels in lung tissue and milder clinical features (eg, less weight loss) with Omicron compared with other variants; this provides further support that Omicron infection may be intrinsically less severe [74-76].

●Impact on diagnostic testing – This is discussed in detail elsewhere. (See "COVID-19: Diagnosis", section on 'Impact of SARS-CoV-2 mutations/variants on test accuracy'.)

Immune responses following infection — Protective SARS-CoV-2-specific antibodies and cell-mediated responses are induced following infection. Some of these responses can be detected for at least a year following infection.

●Humoral immunity – Following infection with SARS-CoV-2, most patients develop detectable serum antibodies to the receptor-binding domain of the viral spike protein and associated neutralizing activity [77,78]. However, the magnitude of antibody response may be associated with severity of disease, and patients with mild infection may not mount detectable neutralizing antibodies [79,80]. When neutralizing antibodies are elicited, they generally decline over several months after infection, although studies have reported detectable neutralizing activity up to 12 months [81-87]. Other studies have also identified spike- and receptor-binding domain memory B cells that increased over the few months after infection as well as spike protein-specific plasma cells, and these findings suggest the potential for a long-term memory humoral response [81,83,84,88]. Although detectable antibodies and neutralizing activity have been associated with protection from subsequent infection [89-93], humoral responses after infection with one variant do not necessarily provide strong protection against other variants. (See 'Risk of reinfection' below.)

●Cell-mediated immunity – Studies have also identified SARS-CoV-2-specific CD4 and CD8 T-cell responses in patients who had recovered from COVID-19 and in individuals who had received COVID-19 vaccination, which suggest the potential for a durable T-cell immune response [81,88,94,95].

Both humoral and cell-mediated responses to infection can be attenuated in patients with immunocompromising conditions, depending on the specific deficit.

EPIDEMIOLOGY

Geographic and temporal distribution — Since the first reports of SARS-CoV-2, infection has spread to every corner of the globe, with COVID-19 occurring on all continents.

Infections occur throughout the year worldwide. Although peaks of cases and hospitalizations occur, particularly in the winter and to a lesser degree in the summer in the Northern Hemisphere, cases occur year-round.

As a comparison, the widely circulating common cold coronaviruses peak one to two times per year [96]. While highest case numbers tend to be seen January through March in temperate areas [2,97], a study from Malawi found the largest peaks in August through September and suggests the need for hyperlocal case counting of coronavirus infections [98]. (See "Common cold coronaviruses", section on 'Seasonality'.)

Risk for severe disease — Older age, certain medical comorbidities, including immunocompromising conditions, pregnancy, and lack of vaccination have been associated with an increased risk for severe COVID-19. These factors are discussed in detail elsewhere. (See "COVID-19: Clinical features", section on 'Risk factors for severe illness' and "COVID-19: Clinical features", section on 'Fatality and mortality rates'.)

Risk of reinfection — Following emergence of the Omicron variant and its sublineages, reinfections have been increasingly common, especially more than 180 days after the previous infection [99]. This mirrors what has been shown for the common cold coronaviruses, where reinfections are common starting around six months [96].

Prior infection with pre-Omicron variants provides poor long-term protection against subsequent Omicron infection; in one meta-analysis, it was estimated to reduce the risk by approximately 35 percent after 40 weeks [100]. Infection with one Omicron sublineage also does not prevent reinfection with a second Omicron sublineage; the risk depends on how closely the sublineages are related (and thus how likely one sublineage evades immunity from a different one), as well as the interval since the prior infection [101,102]. In a study of reinfections in the United States, by the end of 2022, when Omicron sublineage BQ.1/BQ.1.1 was circulating, half of reinfections occurred in individuals who were previously infected when a different Omicron sublineage was circulating [103].

Most reinfections are mild [104]. As an example, in a study from Qatar, the odds of severe disease among 1304 individuals with reinfection was 0.12 compared with age-, sex-, and infection date-matched individuals with an initial infection [105]; there were no cases of critical illness or death among the reinfection group (compared with 28 and 7, respectively, in the initial infection group). Systematic reviews suggest that prior infection is associated with a 75 to 86 percent lower risk of severe illness or hospitalization with a subsequent infection [104,106].

Nevertheless, reinfections that are more severe than the initial infection as well as fatal reinfections can occur [107-109]. Severe SARS-CoV-2 reinfections most frequently occur in immunocompromised individuals, including those being treated for cancer [110].

TRANSMISSION

Person-to-person transmission — Transmission of SARS-CoV-2 requires an index case with a sufficiently high respiratory tract viral load, a susceptible secondary contact, and environmental factors that favor transmission, like poor ventilation. Infection requires that viable viral particles make direct contact with mucous membranes in the eyes, nose, mouth, or respiratory tract.

Respiratory/airborne transmission as primary route — The predominant route of spread is person-to-person transmission through a respiratory route. Short-range aerosol transmission, in which an index patient transmits infection to individuals in close proximity, accounts for most spread. Longer-range transmission, while possible, is less likely because aerosols (and therefore the viral particles suspended on them) are rapidly diluted with distance and time, which decreases the infectious dose. However, permissive environmental conditions, such as poor ventilation or direct airflow patterns between a case and a contact, may lead to an increased risk of transmission at great distances.

Numerous epidemiologic studies have examined the transmission routes of SARS-CoV-2 and illustrated these key features [111]. As an example, a study from China showed that close proximity during train travel (adjacent seat to index case) and more co-travel time were the primary risk factors for transmission [112]. The risk of infection with close contact is further discussed below. (See 'Greatest risk with close contact' below.)

While proximity to an index case was rapidly recognized as a major factor in risk for SARS-CoV-2 infection, long-range transmissions or transmissions in poorly ventilated areas have also been well documented. Very-long-range transmission is also possible when airflow routes carry virus from index to secondary cases; examples of this phenomenon included transmission between individuals in different rooms at a quarantine hotel in Hong Kong who had no direct contact [113] and transmission across different floors in an apartment complex in South Korea connected by nonfunctional bathroom air vents through which kitchen fans circulated contaminated air [114].

Detailed study of the transmission of SARS-CoV-2 completely changed the science of respiratory pathogen transmission [115]. Previously, transmission was believed to be dichotomous: some pathogens were thought to be suspended on large respiratory droplets that fall to the ground quickly after being expelled whereas other pathogens were thought to be suspended on smaller particles, or aerosols, that remained airborne for longer times and distances. In this model, proximity was the key determinant of droplet, but not aerosol, transmission. Most respiratory pathogens were considered to spread through a droplet route. However, the above findings made clear that SARS-CoV-2 was not spreading like a typical "droplet" pathogen. Instead, the primary mode of SARS-CoV-2 transmission (and likely many other respiratory pathogens) is through an "airborne" route, with infectious virions suspended and carried through time and space on tiny aerosol particles.

The implications of SARS-CoV-2 transmission on infection control in hospital settings are discussed in detail elsewhere. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection", section on 'Infection prevention in the health care setting'.)

Minimal role of other person-to-person routes — SARS-CoV-2 has been detected in nonrespiratory specimens, including stool, blood, ocular secretions, and semen [116-123]. These do not significantly contribute to spread.

Several reports have described detection of SARS-CoV-2 RNA from stool specimens, even after viral RNA could no longer be detected from upper respiratory specimens [119,120], and replicative virus has been cultured from stool in rare cases [117,124]. Scattered reports of clusters in a residential building and in a dense urban community with poor sanitation have suggested the possibility of transmission through aerosolization of virus from sewage drainage [125,126]. However, according to a joint World Health Organization (WHO)-China report, transmission through the fecal-oral route did not appear to be a significant factor in the spread of infection [127]. Many similar clusters are likely due to inadequate or nonfunctioning common ventilation systems [114].

Detection of SARS-CoV-2 RNA in blood has also been reported in some but not all studies that have tested for it [116,117,120,128,129]. However, the likelihood of bloodborne transmission (eg, through blood products or needlesticks) is low [130]. (See "Blood donor screening: Laboratory testing", section on 'Emerging infectious disease agents'.)

There is also no evidence that SARS-CoV-2 can be transmitted through contact with nonmucous membrane sites (eg, abraded skin).

In contrast, transmission of SARS-CoV-2 through lung transplantation has been reported [131]. For this reason, most centers do not transplant lungs from known SARS-CoV-2 positive donors. The only confirmed donor-derived SARS-CoV-2 infections among solid organ transplant recipients have been from lung transplantations, and non-lung solid organ transplantation from SARS-CoV-2-positive donors appears safe with minimal risk of transmission to the recipient or involved medical staff [132-134]. (See "COVID-19: Issues related to solid organ transplantation", section on 'Risk of transmission'.)

The risk of vertical transmission of SARS-CoV-2 is discussed elsewhere. (See "COVID-19: Overview of pregnancy issues", section on 'Risk of vertical transmission'.)

Viral shedding and period of infectiousness — The period of infectiousness is the time a person is contagious during infection. The potential to transmit SARS-CoV-2 begins prior to the development of symptoms (presymptomatic transmission) and generally lasts through approximately 10 days of illness, as discussed below. Transmission after that point is unlikely, particularly from immunocompetent persons who do not have severe infection.

●Period of greatest infectiousness – When a new SARS-CoV-2 infection occurs, the respiratory tract viral load rises rapidly over several days to a peak and then falls rapidly over about a week. People with SARS-CoV-2 infection are more likely to be contagious within the first 7 to 10 days of infection, when viral RNA levels from upper respiratory specimens are the highest and infectious virus is most likely detectable [77,78,135-141]. This is supported by data evaluating the duration of transmission risk. One modeling study, in which the mean serial interval between the onset of symptoms among 77 transmission pairs in China was 5.8 days, estimated that infectiousness peaked between two days before and one day after symptom onset and declined within seven days [136]. In another study that evaluated over 2500 close contacts of 100 patients with COVID-19 in Taiwan, all of the 22 secondary cases had their first exposure to the index case within six days of symptom onset; there were no infections documented in the 850 contacts whose exposure was after this interval [142].

Most of these data were collected during the first year of the pandemic. While the general viral load trajectory has remained largely constant for immunocompetent individuals since the emergence of SARS-CoV-2, the relationship of the peak viral load to symptom onset has shifted. Specifically, subsequent data on the Omicron variant suggest that the peak of viral RNA and greatest likelihood of infectious virus shedding may occur slightly later, at three to six days after symptom onset, and with a shorter presymptomatic infectious period but a longer number of infectious days after symptom onset [143,144]. Nevertheless, the median duration that infectious Omicron virus was detectable in nasal specimens ranged from three to five days following diagnosis, and infectious virus was rarely detected more than 10 days after symptom onset, suggesting that transmission after this period remains unlikely with Omicron [145,146].

●Prolonged viral RNA detection does not indicate prolonged infectiousness – The duration of viral RNA shedding is variable and may increase with age and the severity of illness [78,120,147-153]. In a review of 28 studies, the pooled median duration of viral RNA detection in respiratory specimens was 18 days following the onset of symptoms; in some individuals, viral RNA was detected from the respiratory tract several months after the initial infection [152]. Detectable viral RNA, however, does not necessarily indicate the presence of infectious virus, and there appears to be a threshold of viral RNA level below which infectiousness is unlikely.

As an example, in a study of nine patients with mild COVID-19, infectious virus was not detected from respiratory specimens when the viral RNA level was <10⁶ copies/mL [78]. In other studies, infectious virus has only been detected in respiratory specimens with high concentrations of viral RNA. Such high viral RNA concentrations are reflected by lower numbers of reverse transcriptase polymerase chain reaction (RT-PCR) amplification cycles necessary for detection. Depending on the study, the cycle threshold (Ct) for specimen culture positivity may vary from <24 to ≤32 [154,155]. Isolation of infectious virus from upper respiratory specimens more than 10 days after illness onset has only rarely been documented in patients who had nonsevere infection and whose symptoms have resolved [78,154-159].

●Persistent or chronic infections in immunocompromised patients – Prolonged infections with isolation of infectious virus from respiratory specimens for several months following initial infection have been described in people with certain immunocompromising conditions [21,160-165]. The rate of viral clearance is related to the nature and severity of the underlying immunodeficiency. As an example, in a study that tested nasal specimens longitudinally in 56 immunocompromised individuals and 184 immunocompetent individuals with SARS-CoV-2 infection, hematologic malignancy or transplant receipt was associated with prolonged isolation of virus (median 40 days versus 7 days among immunocompetent individuals) [165]. In contrast, the duration of viral isolation in patients with other immunocompromising conditions (eg, primary B-cell deficiency, use of immunosuppressing agents, such as B-cell inhibitors or TNF-alpha inhibitors, for autoimmune conditions) was comparable to that in immunocompetent individuals.

Risk of transmission depends on exposure type — The risk of transmission from an individual with SARS-CoV-2 infection varies by the type and duration of exposure, use of preventive measures, immune status of the exposed individual, and other individual factors (eg, the amount of virus in respiratory secretions) [166]. Many individuals do not transmit SARS-CoV-2 to anyone else, and epidemiologic data suggest that the minority of index cases result in the majority of secondary infections [167-169].

Greatest risk with close contact — The risk of transmission after contact with an individual with COVID-19 increases with the closeness and duration of contact and appears highest with prolonged contact in indoor settings. Thus, most secondary infections have been described in the following settings:

●Among household contacts [170-174]. In a systematic review of 58 studies published from June 2021 to March 2022, the secondary household attack rate during circulation of different variants was 36 percent for the Alpha variant, 29.7 percent for Delta, and 43 percent for Omicron [174]. During Omicron prevalence, vaccination status of either the index case or household contact was not associated with a statistically significant difference in secondary attack rate. However, other potential features that could impact household transmission rates (such as isolation from other household members) were not accounted for. (See 'Omicron (B.1.1.529) and its sublineages' above.)

Within households, spouses or significant others have the highest secondary infection rates [170]. Nevertheless, children and adolescents can also serve as index cases for secondary household infections [175-178]. (See "COVID-19: Clinical manifestations and diagnosis in children", section on 'Transmission'.)

●In congregate settings where individuals are residing or working in close quarters (eg, hospitals when personal protective equipment is not used [179], long-term care facilities [180], cruise ships [181], homeless shelters [182,183], detention facilities [184,185], college dormitories [186], and food processing facilities [187,188]). Shared patient rooms in health care settings are a high-risk environment for transmission of SARS-CoV-2 between an index and a secondary case. One study reported that nearly 40 percent of patients tested positive within 14 days of exposure to a roommate with infection [189]. After universal masking became widespread during the pandemic, residual transmissions between health care workers were often traced to social interactions in break rooms and nonclinical areas or during shared meals [190].

Although transmission rates are highest in household and congregate settings, frequently reported clusters of cases after social or work gatherings also highlight the risk of transmission through close, nonhousehold social contact [191-194]. Going to restaurants and other drinking or eating establishments has also been associated with a higher likelihood of infection, likely because of the difficulty with mask-wearing and distancing in such settings [195,196]. (See 'Wearing masks in the community' below.)

Traveling with an individual with COVID-19 is also a high-risk exposure [112,197-199], as it generally results in close contact for a prolonged period.

The risk of transmission in outdoor settings is substantially lower than indoors [200].

Superspreading events — All variants of SARS-CoV-2 have been associated with heterogeneous transmission dynamics, with different risks of transmission from different index cases. Superspreading events were a major feature of such transmission dynamics. These events, in which a large number of cases can be traced back to a single index case or a single common exposure location, were thought to be major drivers of the pandemic [166,167,201,202].

In uniform transmission dynamics with virus that has a reproduction number (R0) of 2, an index case transmits to two secondary cases which each transmit to two tertiary cases. In contrast, with heterogenous transmission, an index case might transmit to two secondary cases, but those secondary cases could transmit differently, with one transmitting to four tertiary cases and the other transmitting to no additional cases.

Variable amounts of virus in respiratory secretions may contribute to the variable risk of transmission from different individuals [203,204]. In an observational study that included 282 individuals with COVID-19 who had undergone respiratory tract viral RNA quantification as part of a trial and 753 of their close contacts, transmission was identified from only 32 percent of index patients [203]. Higher respiratory tract RNA levels (taken at a median of four days after symptom onset) were independently associated with higher secondary attack rates.

Superspreading events have been mainly described following prolonged group exposure in an enclosed, usually crowded, indoor space. As an example, in an outbreak among a choir group, 33 confirmed and 20 probable cases were identified among 61 members who attended a practice session with a symptomatic index case [191]. This outbreak also highlighted the possibility of a high transmission risk through singing in close proximity.

Asymptomatic or presymptomatic transmission — Transmission of SARS-CoV-2 may occur from symptomatic individuals, individuals who remain asymptomatic throughout the course of infection, or individuals without symptoms at the time of transmission, but who later develop symptoms in the course of infection (“presymptomatic transmission”) [205-211]. Since Omicron sublineage viruses are associated with a shorter presymptomatic period, with symptom onset occurring sooner after the initial increase in respiratory tract viral load [212], there is likely less presymptomatic transmission with Omicron sublineages compared with prior SARS-CoV-2 viruses.

The risk of transmission from a persistently asymptomatic individual appears less than that from one who is symptomatic [171,176,213-216]. As an example, in an analysis of 628 COVID-19 cases and 3790 close contacts in Singapore, the risk of secondary infection was 3.85 times higher among contacts of a symptomatic individual compared with contacts of an asymptomatic individual [217]. Similarly, in an analysis of American passengers on a cruise ship that experienced a large SARS-CoV-2 outbreak, SARS-CoV-2 infection was diagnosed in 63 percent of those who shared a cabin with an individual with asymptomatic infection, compared with 81 percent of those who shared a cabin with a symptomatic individual and 18 percent of those without a cabinmate [215].

The biologic basis for transmission from persistently asymptomatic or presymptomatic patients is supported by a study of a SARS-CoV-2 outbreak (with the wild-type SARS-CoV-2 virus) in a long-term care facility, in which infectious virus was cultured from RT-PCR-positive upper respiratory tract specimens as early as six days prior to the development of typical symptoms [218]. The levels and duration of viral RNA in the upper respiratory tract of asymptomatic patients are also similar to those of symptomatic patients [219].

Incubation period — The time from exposure to infection is discussed in detail elsewhere. (See "COVID-19: Clinical features", section on 'Incubation period'.)

Potential but uncommon routes of transmission

Environmental contamination — Virus present on contaminated surfaces is a possible but unusual source of infection if susceptible individuals touch these surfaces and then transfer infectious virus to mucous membranes in the mouth, eyes, or nose. It may be more likely a potential source of infection in settings where there is heavy viral contamination (eg, in an infected individual's household or in health care settings).

Extensive SARS-CoV-2 RNA contamination of environmental surfaces in hospital rooms and residential areas of patients with COVID-19 has been described [220-222]. In a study from Singapore, viral RNA was detected on nearly all surfaces tested (handles, light switches, bed and handrails, interior doors and windows, toilet bowl, sink basin) in the airborne infection isolation room of a patient with symptomatic mild COVID-19 prior to routine cleaning [220]. Viral RNA was not detected on similar surfaces in the rooms of two other symptomatic patients following routine cleaning (with sodium dichloroisocyanurate). Of note, viral RNA detection does not necessarily indicate the presence of infectious virus [78].

It is unclear how long SARS-CoV-2 can persist on surfaces [223-225]; other coronaviruses have been tested and may survive on inanimate surfaces for up to six to nine days without disinfection [224]. However, various disinfectants (including ethanol at concentrations between 62 and 71%) can inactivate several coronaviruses related to SARS-CoV-2 within one minute [223]. Simulated sunlight has also been shown to inactivate SARS-CoV-2 over the course of 15 to 20 minutes in experimental conditions, with higher levels of ultraviolet-B (UVB) light associated with more rapid inactivation [226]. Based on data concerning other coronaviruses, duration of viral persistence on surfaces also likely depends on the ambient temperature, relative humidity, and the size of the initial inoculum [227].

Animal contact — SARS-CoV-2 infection is thought to have originally been transmitted to humans from an animal host, but the ongoing risk of transmission through animal contact is likely minimal. There is no evidence suggesting animals (including domesticated animals) are a major source of infection in humans.

SARS-CoV-2 infection has been described in animals in both natural and experimental settings. There have been rare reports of animals with SARS-CoV-2 infection (including asymptomatic infections in dogs and symptomatic infections in felines) following close contact with a human with COVID-19 [228-231]. Moreover, asymptomatic, experimentally infected domestic cats may transmit SARS-CoV-2 to cats they are caged with [232]. The risk of infection may vary by species. In one study evaluating infection in animals after intranasal viral inoculation, SARS-CoV-2 replicated efficiently in ferrets and cats; viral replication was also detected in dogs, but they appeared to be less susceptible overall to experimental infection [233]. Pigs and poultry were not susceptible to infection. Mink appear highly susceptible to SARS-CoV-2; outbreaks on mink farms have been reported in Europe and the United States, and in this setting, suspected cases of mink-to-human transmission have been described [234-236]. In view of these findings, mink on farms in both the Netherlands and Denmark have been culled. Hamster-to-human transmission resulting in a large cluster of human cases has also been described [237]. Sustained SARS-CoV-2 infections occur in white-tailed deer, which has become a newer animal reservoir for the virus, though these do not regularly transmit back to humans [18,238].

PREVENTION

Infection control in the health care setting — In locations where community transmission is widespread, preventive strategies for all individuals in a health care setting are warranted to reduce potential exposures. Additional measures are warranted for patients with suspected or confirmed COVID-19. Infection control in the health care setting is discussed in detail elsewhere. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection", section on 'Infection prevention in the health care setting'.)

Personal preventive measures — In the setting of community transmission of SARS-CoV-2 and other respiratory viruses, the following general measures can help prevent infection [239]:

●Pre-exposure prophylaxis with vaccination. (See "COVID-19: Vaccines", section on 'Dose and interval (for immunocompetent individuals)'.)

For certain immunocompromised patients, other pre-exposure prophylactic interventions may be options. (See 'Limited role for monoclonal antibodies in selected patients' below.)

●Ensuring adequate ventilation of indoor spaces. This includes opening windows and doors, placing fans in front of windows to exhaust air to the outside, running heating/air conditioning fans continuously, and using portable high-efficiency particulate air (HEPA) filtration systems [240,241].

●Hand washing and respiratory hygiene (eg, covering the cough or sneeze). Use of hand sanitizer that contains at least 60% alcohol is a reasonable alternative to hand washing if the hands are not visibly dirty. In one study, SARS-CoV-2 remained viable on the skin for about nine hours but was completely inactivated within 15 seconds of exposure to 80% alcohol [242].

●If symptoms suggestive of COVID-19 (table 2) occur, staying home away from others and getting tested for SARS-CoV-2. (See "COVID-19: Diagnosis", section on 'Diagnostic approach'.)

●Avoiding close contact with individuals who have or may have COVID-19. If levels of community transmission are high, avoiding crowds and close contact with other people outside of the household (particularly in poorly ventilated indoor settings) may be reasonable to reduce the risk of exposure. (See 'Social/physical distancing' below.)

●Wearing masks, depending on the level of community transmission and the individual risk for severe infection. (See 'Wearing masks in the community' below.)

These preventive measures are recommended for all individuals in locations where SARS-CoV-2 is circulating and are particularly important for individuals who have immunocompromising conditions and are at higher risk for severe infection.

Wearing masks in the community

When to wear a mask and what type — Local guidelines on mask-wearing depend on the level of community transmission and vaccination rates.

●WHO recommendations – The World Health Organization (WHO) recommends mask-wearing as part of a comprehensive approach to reducing SARS-CoV-2 transmission in either indoor or outdoor settings where there is widespread transmission and social distancing is difficult as well as indoor settings with poor ventilation (regardless of ability to distance) [243].

The WHO recommends medical or nonmedical masks (including homemade multilayered masks) for most individuals and has issued standards for the ideal composition of a cloth mask to optimize fluid resistance and filtration efficiency [244]. However, it specifically recommends medical masks for individuals with symptoms consistent with COVID-19, for individuals at risk for severe COVID-19 (eg, individuals >60 years old or with high-risk underlying conditions) when in public settings where distancing is not feasible, and for household contacts of individuals with suspected or confirmed COVID-19 when in the same room [243].

●CDC recommendations – In the United States, the Centers for Disease Control and Prevention (CDC) includes mask-wearing as an important prevention strategy to reduce the risk of COVID-19 and other viral respiratory illnesses [239]. It notes that masking may be particularly helpful for protection when SARS-CoV-2 and other respiratory viruses are circulating at high levels or for those with risk factors for severe illness. They are also helpful to prevent spread by people with recent COVID-19 exposure who may have early, asymptomatic infection. Mask-wearing for individuals with infection is discussed in detail elsewhere. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection", section on 'Isolation at home'.)

When an individual chooses to wear a mask, the CDC suggests a mask with the highest filtration efficacy that fits well and that one can wear reliably over the mouth and nose [245]. When fit tightly around the face, respirators (eg, N95) have the highest filtration efficacy, followed by disposable medical masks. In general, cloth masks have the lowest filtration efficacy, although cloth masks made of several layers of tightly woven fabric can approach the filtration efficacy of medical masks [246,247]. The importance of filtration efficacy increases in situations in which the risk of exposure is high (eg, prolonged close contact indoors or in vehicles with people outside the household, particularly if other people are unmasked) or for individuals who are at risk for severe COVID-19. Ultimately, however, consistent and correct use is the most important aspect of mask use, as incorrect use or poor fit diminishes the value of high filtration efficacy of the material.

When advising patients on the use of masks, clinicians should counsel them to avoid touching the eyes, nose, and mouth when putting on or removing the mask, to practice hand hygiene before and after handling the mask, and to launder cloth masks routinely. Clinicians should also emphasize that the mask does not diminish the importance of other preventive measures, such as vaccination. Patients can also be counseled that masks have not been associated with impairment in gas exchange, including among patients with underlying lung disease [248,249].

Rationale — The primary objective for wearing masks in the community is to prevent transmission from individuals with infection by containing their respiratory secretions. Masks can also reduce exposure to SARS-CoV-2 for the wearer.

●Source control and transmission reduction – Multiple observational studies support the use of masks to provide source control and reduce transmission in the community [246,250-261]. In epidemiologic studies, government-issued mask mandates and high rates of self-reported mask-wearing have each been associated with decreased community incidence rates and, in some cases, decreased COVID-19 hospitalization rates [257,262-264]; lifting of universal mask mandates has conversely been associated with increased case rates [265]. In a meta-analysis of six observational studies, mask-wearing was associated with a 53 percent reduction in the incidence of COVID-19 [259]. Modeling studies have also suggested that high adoption of mask-wearing by the general public can reduce transmission, even if masks are only moderately effective in containing infectious respiratory secretions [266,267].

Nevertheless, efficacy of masks has been difficult to demonstrate consistently in clinical trials. In a meta-analysis of six trials that did not demonstrate reductions in laboratory-confirmed influenza or SARS-CoV-2 infection with wearing medical masks in the community (risk ratio [RR] 1.01, 95% CI 0.72-1.42), only two of those trials evaluated SARS-CoV-2 transmission [268]. One of those was a cluster-randomized trial in Bangladesh, in which villages that received free masks as well as behavioral and social interventions to promote masks had increased mask use (40 versus 14 percent in control villages) and, among those who received medical masks, an associated 11 percent relative reduction in SARS-CoV-2 seroprevalence that was not statistically significant (adjusted RR 0.89, 95% CI 0.78-1.01) [269]. The other trial, from Denmark, is discussed below.

●Prevent exposure – Mask-wearing in the community may protect the wearer; in several observational studies, consistent mask-wearing, particularly with medical masks or respirators, has been associated with a lower risk of infection [270-273]. In a report of 382 service members who were surveyed about personal preventive strategies in the setting of a SARS-CoV-2 outbreak on a United States Navy aircraft carrier, self-report of wearing a face cover was independently associated with a lower likelihood of infection (odds ratio [OR] 0.3), as were avoiding common areas (OR 0.6) and observing social distancing (OR 0.5) [270]. In a retrospective analysis of 1060 individuals identified by contact tracing following clusters of infections in Thailand, wearing a mask all the time was associated with a lower odds of infection compared with not wearing a mask; there was no significant association between wearing a mask some of the time and infection rate [271]. In contrast, a randomized trial from Denmark did not identify a decreased rate of infection among individuals who were provided with surgical masks and advised to wear them when outside of the house for a month (1.8 versus 2.1 percent among individuals who were not given masks or the recommendation) [274]. However, the low rate of community transmission (as reflected by the low overall infection rate) may have made it difficult to detect a meaningful difference. Additionally, much SARS-CoV-2 transmission occurs in the household, where masking is seldom practiced or may be used too late after a sick household contact enters the home.

●Filtration efficacy – Filtering facepiece respirators (FFR) have the highest filtration efficacy. In the United States, the prototypical FFR is the N95 respirator, which filters at least 95 percent of 0.3 micrometer particles. Medical masks have lower filtration efficacy, which depends on how closely the mask lies against the face. In one study, medical masks with ties versus ear loops filtered 72 and 38 percent of particles, respectively (approximately 0.02 to 3.00 micrometers) [275]. Other strategies to improve the fit of a medical mask, such as using a cloth mask over it or knotting the ear loops to eliminate gaps, also appear to increase filtration efficacy [276]. Studies on the filtration efficacy of fabrics suggest that certain fabrics (eg, tea towel fabric [termed dish towel fabric in the United States], cotton-polypropylene blends), particularly when double-layered, can approach the filtration efficacy of medical masks [246,277-279]. In an experimental model, universal masking with a three-ply cotton mask was shown to substantially reduce aerosol exposure [241]. Tight-weave fabric, two or more layers, and a tight fit are essential for adequate filtration.

Despite the variability in filtration efficacy of different masks (respirators, medical masks, cloth masks) in experimental settings, data on clinical efficacy differences in preventing transmission of SARS-CoV-2 are lacking.

Eye protection — Although eye protection is recommended in health care settings, the role of face shields or goggles in addition to masks to further reduce the risk of infection in the community is uncertain [280,281]. Data are mixed on whether wearing eyeglasses daily is associated with reduced risk of infection [282,283]; eyeglasses are generally considered insufficient for eye protection.

In contrast, adding eye protection as a component of personal protective equipment in health care settings has been associated with decreased SARS-CoV-2 risk. As an example, in a systematic review of 13 studies, eye protection was associated with a lower risk of health care-related infections with SARS-CoV-2 and related coronaviruses [254]. Eye protection in the hospital setting is discussed in detail elsewhere. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection", section on 'Type of PPE'.)

Social/physical distancing — In locations where there are high levels of community transmission of SARS-CoV-2, individuals are advised to practice social or physical distancing by avoiding crowded spaces or otherwise maintaining distance from other people outside their household, particularly in indoor, poorly ventilated settings. The optimal distance is uncertain; the WHO recommends a minimum distance of three feet (one meter). The rationale is to minimize close-range contact with an individual with infection, which is thought to be the primary risk of exposure to SARS-CoV-2. (See 'Person-to-person transmission' above.)

Physical distancing is independently associated with a reduced risk of SARS-CoV-2 transmission [254,284-286]. In a meta-analysis of observational studies evaluating the relationship between physical distance and transmission of SARS-CoV-2, SARS-CoV, and Middle East Respiratory Syndrome coronavirus (MERS-CoV), proximity and risk of infection were closely associated, and the infection rate was higher with contact within three feet (one meter) compared with contact beyond that distance (12.8 versus 2.6 percent) [254]. A distance more than six feet (two meters) was associated with further reduction in transmission.

Screening in selected high-risk settings — Testing asymptomatic individuals without known exposure is not routinely warranted, although the practice may be useful in high-risk congregate settings, such as long-term care facilities, shelters, and correctional facilities, when community transmission of SARS-CoV-2 is prevalent.

Screening for SARS-CoV-2 infection with serial viral testing can quickly identify cases so that infected individuals can be isolated, contacts can be quarantined, and outbreaks can be prevented [287,288]. Both nucleic acid amplification tests (NAATs) and antigen tests have been used for serial screening. Although antigen tests are generally less sensitive than NAAT, modelling studies have suggested that if the frequency of testing is high enough, tests with lower sensitivity can be successfully used to reduce cumulative infection rates [289,290]. Accessibility and fast turnaround time are also important features of a useful screening test. (See "COVID-19: Diagnosis", section on 'In outbreak settings'.)

Testing-based screening strategies have the advantage of identifying asymptomatic or presymptomatic infections. Several studies have highlighted the limitations of symptom-based screening methods because of the high proportion of asymptomatic cases [291,292]. (See "COVID-19: Clinical features", section on 'Asymptomatic infections'.)

Other public health measures — Throughout the world, countries have employed various nonpharmaceutical interventions to reduce transmission, primarily used during the height of the pandemic before the era of widespread population immunity. In addition to personal preventive measures (vaccination, hand and respiratory hygiene, ventilation, masking), transmission reduction strategies have included:

●Social/physical distancing orders

●Stay-at-home orders

●School, venue, and nonessential business closure

●Bans on public gatherings

●Travel restriction with exit and/or entry screening

●Aggressive case identification and isolation (separating individuals with infection from others)

●Contact tracing and quarantine (separating individuals who have been exposed from others)

These measures had been associated with reductions in the incidence of SARS-CoV-2 infection, with epidemiologic studies showing reductions in cases, and in some situations, COVID-19-related deaths following implementation of these mitigation measures [259,293-302].

Implementation of these measures varies widely by country as well as over time, depending on regional rates of infection. Specific recommendations on global travel are available on the WHO website.

Pre-exposure prophylaxis

Vaccination — SARS-CoV-2 vaccination prevents infection. The protective effect on infection was strongest before the emergence of SARS-CoV-2 variants of concern. Subsequently, protective efficacy against infection decreased due to at least three factors: intrinsic replication advantage of newer variants [303], waning immunity (the natural and expected decline of vaccine-induced antibody titers over time) [304], and antigenic shift that results in escape from vaccine-induced antibody responses.

Despite these factors, the COVID-19 vaccines continue to protect against severe disease and, with updated formulations and boosting schedules, likely still provide modest protection against all infections.

Recommendations on COVID-19 vaccination and its benefits are discussed in detail elsewhere. (See "COVID-19: Vaccines", section on 'Approach to vaccination in the United States' and "COVID-19: Vaccines", section on 'Benefits of vaccination'.)

Limited role for monoclonal antibodies in selected patients — Although COVID-19 vaccination is the optimal method of pre-exposure prophylaxis in the general population, certain individuals at risk for severe disease may not benefit maximally from vaccination because of suboptimal immune response. Monoclonal antibodies targeting SARS-CoV-2 have been used as supplemental preventive agents (in addition to vaccination) in such patients, although their utility is generally time-limited because ongoing viral evolution results in emergent variants that the monoclonal antibody no longer recognizes.

The availability of active monoclonal antibodies has varied since the emergence of SARS-CoV-2:

●In March 2024 in the United States, pemivibart, a novel monoclonal antibody product, received emergency use authorization (EUA) for pre-exposure prophylaxis in individuals age 12 years or older (weighing at least 40 kg) who have moderate-to-severe immunocompromising conditions (table 3), no active SARS-CoV-2 infection, and no recent exposure [305].

We suggest pre-exposure prophylaxis with pemivibart in eligible patients at particularly high risk of suboptimal vaccine response and severe COVID-19, including those with active hematologic malignancy, recent hematopoietic stem cell transplantation, or a history of solid organ transplantation (particularly if performed recently or with recent treatment for organ rejection). Pemivibart is authorized for use when the prevalence of variants with substantially reduced susceptibility is ≤90 percent; however, the expected benefits of pemivibart decrease as the prevalence of strains with reduced susceptibility increases, even below this 90 percent threshold [305]. Pemivibart has neutralizing activity against JN.1 and many of its descendant lineages (eg, KP.2 and KP.3), which have been the dominant lineages in the United States for most of 2024. Data are limited, but activity against KP.3.1.1 may be substantially reduced [306].

It is given as a 4500 mg intravenous infusion once every three months and should be administered in a setting where health care personnel can evaluate and manage anaphylaxis, a rare adverse effect. Among individuals with a recent history of COVID-19 vaccination, pemivibart should be given at least two weeks after vaccine receipt.

Data on clinical outcomes with pemivibart are pending and the clinical benefit is uncertain. Authorization was based on data demonstrating antibody levels and neutralizing titers against JN.1 following pemivibart administration in immunocompromised patients that were similar to levels achieved with other monoclonal antibodies that were effective against other SARS-CoV-2 variants [305,307]. In addition to anaphylaxis, hypersensitivity or infusion reactions (eg, fever, tachycardia, dyspnea, chest pain, nausea, vasovagal reactions, rash) were noted in trials of pemivibart, in approximately 9 percent of immunocompromised patients.

Globally circulating Omicron sublineages escape neutralization by other monoclonal antibodies that were previously used for prophylaxis (eg, tixagevimab-cilgavimab) or treatment (eg, bamlanivimab-etesevimab, casirivimab-imdevimab, sotrovimab, bebtelovimab, regdanvimab). These agents are considered ineffective and are no longer available in most locations.

Interventions with no preventive role — Various interventions have been evaluated for prevention of COVID-19, but most do not have demonstrated efficacy and should not be used for prevention. Notable examples include:

●Post-exposure prophylaxis with nirmatrelvir-ritonavir – Nirmatrelvir-ritonavir does not appear to be effective for preventing infection following exposure. In a trial of 2736 individuals who had a household exposure to SARS-CoV-2 within 96 hours of randomization, nirmatrelvir-ritonavir for 5 or 10 days did not reduce the rate of confirmed symptomatic SARS-CoV-2 infection over the following two weeks compared with placebo (2.6 and 2.4 versus 3.9 percent; relative risk reduction of 30 percent [95% CI -17 to 58] for 5 days and 36 percent [95% CI -12 to 63] for 10 days) [308]. Most participants were recruited following emergence of the Omicron variant, and approximately 91 percent had anti-SARS-CoV-2 antibodies at baseline. The relatively low rate of secondary infection may have been related to the high level of pre-existing immunity.

●Hydroxychloroquine and ivermectin – Data from placebo-controlled randomized trials indicate that hydroxychloroquine is not effective in preventing infection [309-314]; the WHO specifically recommends against using hydroxychloroquine to prevent COVID-19 [315]. Ivermectin has also been proposed as a potential prophylactic agent, but it has only been evaluated in low-quality unpublished studies [316], and clinical evidence supporting its use is lacking. Furthermore, although ivermectin has been reported to have some activity against SARS-CoV-2 in vitro, plasma levels high enough for antiviral activity cannot be achieved with safe drug doses [317].

●BCG – Bacille Calmette-Guerin (BCG) vaccine was hypothesized to protect against COVID-19 because of its immunomodulatory properties, but in most clinical trials, BCG administration did not reduce the risk of COVID-19. This is discussed in detail elsewhere. (See "Prevention of tuberculosis: BCG immunization and nutritional supplementation", section on 'Effect on risk of respiratory infection and COVID-19 in adults'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: COVID-19 – Index of guideline topics".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topics (see "Patient education: COVID-19 overview (The Basics)" and "Patient education: COVID-19 vaccines (The Basics)" and "Patient education: COVID-19 and pregnancy (The Basics)" and "Patient education: COVID-19 and children (The Basics)" and "Patient education: Long COVID (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Burden of disease – Since the first reports of coronavirus disease 2019 (COVID-19) and identification of the novel coronavirus that causes it, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the infection has spread to every corner of the globe, causing disease year-round. Reinfections are increasingly common. (See 'Epidemiology' above.)

●Variants of concern – Several variants of SARS-CoV-2 have emerged that are notable because of the potential for increased transmissibility. Omicron variant sublineages are associated with a higher risk of reinfection in individuals previously infected with other variants and breakthrough infection in vaccinated individuals, but they are also associated with less severe disease (table 1). (See 'Viral evolution and variants of concern' above.)

●Modes of transmission – Short-range aerosol person-to-person transmission is the primary means of SARS-CoV-2 transmission. When a person with infection coughs, sneezes, or talks, virus suspended on tiny particles can infect a susceptible contact if it is inhaled or makes direct contact with the mucous membranes. The highest risk for infection is with close-range contact; SARS-CoV-2 can also be transmitted over longer distances, particularly in enclosed, poorly ventilated spaces. (See 'Person-to-person transmission' above.)

●Period of infectiousness – Individuals with SARS-CoV-2 infection are most infectious in the earlier stages of infection (starting prior to the development of symptoms). Transmission after 7 to 10 days of illness is unlikely, particularly for otherwise immunocompetent patients with nonsevere infection. Prolonged viral RNA shedding after symptom resolution is not clearly associated with prolonged infectiousness. (See 'Viral shedding and period of infectiousness' above.)

●Personal preventive measures – In settings where there is community transmission of SARS-CoV-2, personal measures to reduce the risk of transmission include vaccination, hand and respiratory hygiene, masking, improving indoor ventilation and avoiding poorly ventilated crowded areas, being vigilant for signs and symptoms of COVID-19, and avoiding close contact with ill individuals. (See 'Personal preventive measures' above and 'Wearing masks in the community' above and 'Social/physical distancing' above and 'Other public health measures' above.)

●Pre-exposure prophylaxis – COVID-19 vaccination is the optimal method of pre-exposure prophylaxis. For selected immunocompromised patients expected to have suboptimal immune response to vaccination (eg, those with active hematologic malignancy, recent stem cell transplantation, or history of solid organ transplantation), we also suggest pre-exposure prophylaxis with the monoclonal antibody pemivibart to reduce the risk of severe COVID-19 (Grade 2C). Supportive data are limited to immunogenicity studies and indirect observational data with other monoclonal antibodies. Pemivibart should only be used if it remains active against the dominant circulating variants. (See 'Pre-exposure prophylaxis' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Kenneth McIntosh, MD, who contributed to earlier versions of this topic review.