Virus World

We analyzed the kinetics and durability of the humoral responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination using >8,000 longitudinal samples collected over a three-year period (April 2020 to April 2023) in the New York City metropolitan area. Upon primary immunization, participants with pre-existing immunity mounted higher antibody responses faster and achieved higher steady-state levels compared to naive individuals. Antibody durability was characterized by two phases: an initial rapid decay, followed by a phase of stabilization with very slow decay resulting in an individual spike binding antibody steady state.

Booster vaccination equalized the differences in antibody levels between participants with and without hybrid immunity, but the antibody titers reached decreased with each successive antigen exposure. Break-through infections increased antibody titers to similar levels as an additional vaccine dose in naive individuals. Our study provides strong evidence for the fact that SARS-CoV-2 antibody responses are long lasting, with an initial waning phase followed by a stabilization phase.

Preprint available at medRxiv (August 28, 2023):

https://doi.org/10.1101/2023.08.26.23294679 

Planas et al analyze the extent and duration of the neutralizing antibody response following vaccination with Pfizer BNT162b2 mRNA in the sera and nasal swabs from individuals with or without Omicron breakthrough infection, finding a short duration of neutralization against BA.5 after boosting and strong IgA response upon breakthrough infection.

Background

Methods

Findings

Conclusions

Study of triple vaccinated people also says Omicron infection does little to reduce chance of catching variant again.  People who caught Covid during the first wave of the pandemic get no boost to their immune response if they subsequently catch Omicron, a study of triple vaccinated people reports. Experts say that while three doses of a Covid jab help to protect individuals against severe outcomes should they catch Omicron, previous infections can affect their immune response. “If you were infected during the first wave, then you can’t boost your immune response if you have an Omicron infection,” said Prof Rosemary Boyton, of Imperial College London, a co-author of the study. The team also found an Omicron infection offered little extra protection against catching the variant again. “When Omicron started flying around the country, people kept saying that’s OK, that will improve people’s immunity,” said Boyton. “What we’re saying is it’s not a good booster of immunity.”  The team said the findings may help to explain why reinfections with Omicron over a short time period have been so frequent, adding the findings were also important for vaccine development.

Writing in the journal Science, the researchers reported how they followed the vaccination and infection experiences of 731 triple vaccinated healthcare workers in the UK from March 2020 to January 2022. The team then used blood samples collected from participants in the weeks after their third dose of vaccine to explore their antibody and T-cell responses towards the Omicron variant, BA.1. The participants varied considerably in terms of their Covid history, including whether they had had a previous Covid infection and, if so, the variant involved. The results suggested that, regardless of the participants’ previous infection history, a few weeks after their third Covid jab their levels of T-cells against Omicron proteins were poor, while levels of antibodies against Omicron proteins were lower than against other variants. But previous infections also mattered. Among other findings the team reported infection with Omicron increased protection against future infection with other variants. However, it only offered a limited boost to protection against another Omicron infection – a response that was actually weakened among those who had also previously had the original strain of the virus.  The team said the results held for both antibody and T-cell responses, and suggested those who caught Covid in the first wave of the pandemic did not gain a boost to their immune response should they subsequently catch Omicron.

The researchers said the finding was a surprise as it was typically assumed that a prior infection, even of a different variant, would act to boost an individual’s immune response. Prof Danny Altmann, another author of the study, said that while it had previously been thought Covid variants such as Omicron had developed mutations in their spike protein that helped them to evade immune responses, the situation was more complex.

“It’s actually worse than that, because the adaptations that the spike [protein] has now are actually inducing a kind of regulation or shutdown of immune response,” he said, adding that while the study looked at responses to the BA.1, similar findings were likely for other subvariants of Omicron. The team added that with people in the UK having had very different histories of Covid infections and vaccinations, the study was important as it suggested this “immune imprinting” would shape subsequent immunity against the next variant. Altmann said that while the continued low levels of hospitalisation and deaths from Covid in the UK, despite high levels of infection, suggested Covid jabs continued to offer protection against death and severe disease, the findings could be important for the development of new vaccines. But he added the findings raised other concerns. “We’re not getting herd immunity, we’re not building up protective immunity to Omicron,” he said. “So we face not coming out the other end of infections and re-infections and breakthrough infections.”

Published in Science (June 14, 2022):

https://doi.org/10.1126/science.abq1841 

The post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection—also referred to as Long COVID—have been described, but whether breakthrough SARS-CoV-2 infection (BTI) in vaccinated people results in post-acute sequelae is not clear. In this study, we used the US Department of Veterans Affairs national healthcare databases to build a cohort of 33,940 individuals with BTI and several controls of people without evidence of SARS-CoV-2 infection, including contemporary (n = 4,983,491), historical (n = 5,785,273) and vaccinated (n = 2,566,369) controls. At 6 months after infection, we show that, beyond the first 30 days of illness, compared to contemporary controls, people with BTI exhibited a higher risk of death (hazard ratio (HR) = 1.75, 95% confidence interval (CI): 1.59, 1.93) and incident post-acute sequelae (HR = 1.50, 95% CI: 1.46, 1.54), including cardiovascular, coagulation and hematologic, gastrointestinal, kidney, mental health, metabolic, musculoskeletal and neurologic disorders.

The results were consistent in comparisons versus the historical and vaccinated controls. Compared to people with SARS-CoV-2 infection who were not previously vaccinated (n = 113,474), people with BTI exhibited lower risks of death (HR = 0.66, 95% CI: 0.58, 0.74) and incident post-acute sequelae (HR = 0.85, 95% CI: 0.82, 0.89). Altogether, the findings suggest that vaccination before infection confers only partial protection in the post-acute phase of the disease; hence, reliance on it as a sole mitigation strategy may not optimally reduce long-term health consequences of SARS-CoV-2 infection. The findings emphasize the need for continued optimization of strategies for primary prevention of BTI and will guide development of post-acute care pathways for people with BTI. A new analysis using the US Department of Veterans Affairs national healthcare databases demonstrates that Long COVID can occur after breakthrough SARS-CoV-2 infection; however, the risk of death attributable to COVID and incidence of post-acute sequelae were substantially reduced (but not fully eliminated) compared to unvaccinated individuals.

Published in Nature Medicine (May 25, 2022):

https://www.nature.com/articles/s41591-022-01840-0 

Mayo Clinic research finds both inoculations have dropped in efficacy, but Pfizer's decline has been much steeper; both remain highly effective against severe illness.  Moderna’s coronavirus vaccine is considerably more effective at repelling the Delta variant of the virus than Pfizer-BioNTech’s inoculation, according to research conducted in several US states by the Mayo Clinic. The study uploaded to medRxiv ahead of peer review this week found that while both vaccines were highly effective in preventing infection in January, before the introduction of Delta — hovering at around 90 percent — by July the effectiveness of both shots had dropped. However, one was still far more effective than the other — while Moderna was down to 76 percent, Pfizer was down to 42%. The study was conducted among over 50,000 patients.  It is not currently known whether the drop in effectiveness is a result of Delta’s ability to bypass the vaccine, an erosion in protection offered over time, or a combination of both factors. Israel, which has vaccinated its population almost exclusively with the Pfizer shot, is currently administering third doses to adults over 60 in the hope of raising protection. According to one top expert Tuesday, this effort may be bearing fruit. 

The Mayo Clinic study found that across multiple states, those inoculated with Pfizer were twice as likely to experience a breakthrough infection despite being vaccinated, as compared to Moderna.  “In Florida, which is currently experiencing its largest COVID-19 surge to date, the risk of infection in July after full vaccination with mRNA-1273 (the Moderna shot) was about 60% lower than after full vaccination with BNT162b2 (Pfizer),” the researchers said. Still, both vaccines appeared to remain highly effective (over 90%) at preventing severe illness. The researchers concluded that “our observational study highlights that while both mRNA COVID-19 vaccines strongly protect against infection and severe disease, further evaluation of mechanisms underlying differences in their effectiveness such as dosing regimens and vaccine composition are warranted.” Israel has predominantly relied on Pfizer’s vaccine to inoculate its population, but has also purchased millions of doses of Moderna’s version. Both companies are currently developing booster shots that will target newer variants such as Delta, but these will take many more months to reach the market. The COVID-19 vaccine is Moderna’s only commercially approved product. It is also developing several vaccines that aim to guard against the flu, Zika and HIV among other viruses. Those are all in early stages of clinical testing, according to its website. The company, which was formed to commercialize mRNA vaccine technology, said it had nearly doubled in size over the past year, from 930 employees to around 1,800. It reported $4.35 billion in total revenue, thanks to the vaccine and some grants.

Research cited available in medRxiv (August 21, 2021):

https://doi.org/10.1101/2021.08.06.21261707 

With early vaccination and outstanding data, country is the world’s real-life COVID-19 lab. “Now is a critical time,” Israeli Minister of Health Nitzan Horowitz said as the 56-year-old got a COVID-19 booster shot on 13 August, the day his country became the first nation to offer a third dose of vaccine to people as young as age 50. “We’re in a race against the pandemic.”  His message was meant for his fellow Israelis, but it is a warning to the world. Israel has among the world’s highest levels of vaccination for COVID-19, with 78% of those 12 and older fully vaccinated, the vast majority with the Pfizer vaccine. Yet the country is now logging one of the world’s highest infection rates, with nearly 650 new cases daily per million people. More than half are in fully vaccinated people, underscoring the extraordinary transmissibility of the Delta variant and stoking concerns that the benefits of vaccination ebb over time. The sheer number of vaccinated Israelis means some breakthrough infections were inevitable, and the unvaccinated are still far more likely to end up in the hospital or die. But Israel’s experience is forcing the booster issue onto the radar for other nations, suggesting as it does that even the best vaccinated countries will face a Delta surge.  His message was meant for his fellow Israelis, but it is a warning to the world. Israel has among the world’s highest levels of vaccination for COVID-19, with 78% of those 12 and older fully vaccinated, the vast majority with the Pfizer vaccine. Yet the country is now logging one of the world’s highest infection rates, with nearly 650 new cases daily per million people. More than half are in fully vaccinated people, underscoring the extraordinary transmissibility of the Delta variant and stoking concerns that the benefits of vaccination ebb over time. The sheer number of vaccinated Israelis means some breakthrough infections were inevitable, and the unvaccinated are still far more likely to end up in the hospital or die.

But Israel’s experience is forcing the booster issue onto the radar for other nations, suggesting as it does that even the best vaccinated countries will face a Delta surge. At the same time, cases in the country, which were scarcely registering at the start of summer, have been doubling every week to 10 days since then, with the Delta variant responsible for most of them. They have now soared to their highest level since mid-February, with hospitalizations and intensive care unit admissions beginning to follow. How much of the current surge is due to waning immunity versus the power of the Delta variant to spread like wildfire is uncertain. What is clear is that “breakthrough” cases are not the rare events the term implies. As of 15 August, 514 Israelis were hospitalized with severe or critical COVID-19, a 31% increase from just 4 days earlier. Of the 514, 59% were fully vaccinated. Of the vaccinated, 87% were 60 or older. “There are so many breakthrough infections that they dominate and most of the hospitalized patients are actually vaccinated,” says Uri Shalit, a bioinformatician at the Israel Institute of Technology (Technion) who has consulted on COVID-19 for the government. “One of the big stories from Israel [is]: ‘Vaccines work, but not well enough.’” “The most frightening thing to the government and the Ministry of Health is the burden on hospitals,” says Dror Mevorach, who cares for COVID-19 patients at Hadassah Hospital Ein Kerem and advises the government. At his hospital, he is lining up anesthesiologists and surgeons to spell his medical staff in case they become overwhelmed by a wave like January’s, when COVID-19 patients filled 200 beds. “The staff is exhausted,” he says, and he has restarted a weekly support group for them “to avoid some kind of PTSD [post-traumatic stress disorder] effect.”

To try to tame the surge, Israel has turned to booster shots, starting on 30 July with people 60 and older and, last Friday, expanding to people 50 and older. As of Monday, nearly 1 million Israelis had received a third dose, according to the Ministry of Health. Global health leaders including Tedros Adhanom Ghebreyesus, director-general of the World Health Organization, have pleaded with developed countries not to administer boosters given that most of the world’s population hasn’t received even a single dose. The wealthy nations pondering or already administering booster vaccines so far mostly reserve them for special populations such as the immune compromised and health care workers. Still, studies suggest boosters might have broader value. Researchers have shown that boosting induces a prompt surge in antibodies, which are needed in the nose and throat as a crucial first line of defense against infection. The Israeli government’s decision to start boosting those 50 and older was driven by preliminary Ministry of Health data indicating people over age 60 who have received a third dose were half as likely as their twice-vaccinated peers to be hospitalized in recent days, Mevorach says. CHS also reported that out of a sample of more than 4500 patients who received boosters, 88% said any side effects from the third shot were no worse, and sometimes milder, than from the second. Yet boosters are unlikely to tame a Delta surge on their own, says Dvir Aran, a biomedical data scientist at Technion. In Israel, the current surge is so steep that “even if you get two-thirds of those 60-plus [boosted], it’s just gonna give us another week, maybe 2 weeks until our hospitals are flooded.” He says it’s also critical to vaccinate those who still haven’t received their first or second doses, and to return to the masking and social distancing Israel thought it had left behind—but has begun to reinstate. Aran’s message for the United States and other wealthier nations considering boosters is stark: “Do not think that the boosters are the solution.”

The short-term effectiveness of a two-dose regimen of the BioNTech/Pfizer mRNA BNT162b2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine was widely demonstrated. However, long term effectiveness is still unknown. A nationwide vaccination campaign was initiated early in Israel, allowing for a real-world evaluation of the interaction between protection and time-from-vaccine. The Delta (B.1.617.2) variant became the dominant strain in Israel in June 2021, as Israel is currently experiencing a new surge of cases. Leveraging the centralized computerized database of Maccabi Healthcare Services (MHS), we assessed the correlation between time-from-vaccine and incidence of breakthrough infection. We found that the risk for infection was significantly higher for early vaccinees compared to those vaccinated later. This preliminary finding should prompt further investigagions into long-term protection against different strains, and prospective clinical trials to examine the effect of a booster vaccine against breakthrough infection.

Available as preprint in medRxiv (July 31, 2021):

https://doi.org/10.1101/2021.07.29.21261317 

This report describes COVID-19 outbreaks associated with large public gatherings in Massachusetts, including COVID-19 vaccine breakthrough infections.

What is already known about this topic?

Variants of SARS-CoV-2 continue to emerge. The B.1.617.2 (Delta) variant is highly transmissible.

What is added by this report?

In July 2021, following multiple large public events in a Barnstable County, Massachusetts, town, 469 COVID-19 cases were identified among Massachusetts residents who had traveled to the town during July 3–17; 346 (74%) occurred in fully vaccinated persons. Testing identified the Delta variant in 90% of specimens from 133 patients. Cycle threshold values were similar among specimens from patients who were fully vaccinated and those who were not.

What are the implications for public health practice?

Jurisdictions might consider expanded prevention strategies, including universal masking in indoor public settings, particularly for large public gatherings that include travelers from many areas with differing levels of SARS-CoV-2 transmission.

Published in MMWR (July 30, 2021): http://dx.doi.org/10.15585/mmwr.mm7031e2 

PM Bennett: Vaccine ‘significantly less’ effective against the Delta variant.  The effectiveness of the Pfizer vaccine against the Delta variant is “weaker” than health officials had hoped, Prime Minister Naftali Bennett said on Friday, as over 1,000 people tested positive for coronavirus and more countries were added to the list of places to which Israelis will be banned from traveling. “We do not know exactly to what degree the vaccine helps, but it is significantly less,” Bennett said.  The prime minister held a meeting of top health officials and ministers to discuss the next steps for managing the virus in light of the numbers in Israel and what Bennett described as “the Delta mutation leaping forward around the world, including in vaccinated countries such as Britain, Israel and the US.” He said that in “Britain, in recent days, we have seen a jump in the number of children who are being hospitalized on a daily basis. This is a development that we are aware of; we are dealing with it rationally and responsibly.” With more than 5.7 million Israelis having received at least one shot of the Pfizer vaccine, the country continues to push for citizens – especially teenagers – to go out and get the jab.

medRxiv - Across 20 vaccine breakthrough cases detected at our institution, all 20 (100%) infections were due to variants of concern (VOC) and had a median Ct of 20.2 (IQR=17.1-23.3). When compared to 5174 contemporaneous samples sequenced in our laboratory, VOC were significantly enriched among breakthrough infections (p < .05).

Preprint available at medRxiv (May 25, 2021):

https://doi.org/10.1101/2021.05.23.21257679

SARS-CoV-2 vaccine immunogenicity varies between individuals, and immune responses correlate with vaccine efficacy. Using data from 1,076 participants enrolled in ChAdOx1 nCov-19 vaccine efficacy trials in the United Kingdom, we find that inter-individual variation in normalised antibody responses against SARS-CoV-2 spike (S) and its receptor binding domain (RBD) at 28 days following first vaccination shows genome-wide significant association with major histocompatibility complex (MHC) class II alleles. The most statistically significant association with higher levels of anti-RBD antibody was HLA-DQB1*06 (P = 3.2 × 10−9), which we replicate in 1,677 additional vaccinees. Individuals carrying HLA-DQB1*06 alleles were less likely to experience PCR-confirmed breakthrough infection during the ancestral SARS-CoV-2 virus and subsequent Alpha-variant waves compared with non-carriers (HR 0.63, 0.42–0.93, P = 0.02).

We identify a distinct S-derived peptide that is predicted to bind differentially to HLA-DQB1*06 compared with other similar alleles, and find evidence of increased spike-specific memory B-cell responses in HLA-DQB1*06 carriers at 84 days following first vaccination. Our results demonstrate association of HLA type with COVID-19 vaccine antibody response and risk of breakthrough infection, with implications for future vaccine design and implementation. Variation in antibody levels elicited by the COVID-19 vaccine ChAdOx1 nCov-19 is linked to specific major histocompatibility complex class II alleles, providing insight into the breadth of immune response among vaccinated individuals.

Published in Nature Medicine (Oct. 13, 2022):

https://doi.org/10.1038/s41591-022-02078-6 

SARS-CoV-2 omicron subvariants BA.1 and BA.2 became dominant in many countries in early 2022. These subvariants are now being displaced by BA.4 and BA.5. While natural infection with BA.1/BA.2 provides some protection against BA.4/BA.5 infection, the duration of this protection remains unknown. We used the national Portuguese COVID-19 registry to investigate the waning of protective immunity conferred by prior BA.1/BA.2 infection towards BA.5. We divided the individuals infected during the period of BA.1/BA.2 dominance (>90% of sample isolates) in successive 15-day intervals and determined the risk of subsequent infection with BA.5 over a fixed period. Compared with uninfected people, one previous infection conferred substantial protection against BA.5 re-infection at 3 months (RR=0.12; 95% CI: 0.11-0.12). However, although still significant, the protection was reduced by two-fold at 5 months post-infection (RR=0.24; 0.23-0.24). These results should be interpreted in the context of vaccine breakthrough infections, as the vaccination coverage in the individuals included in the analyses is >98% since the end of 2021. This waning of protection following BA.1/BA.2 infection highlights the need to assess the stability and durability of immune protection induced with the adapted vaccines (based on BA.1) over time.

Preprint available at medRxiv (August 17, 2022):

https://doi.org/10.1101/2022.08.16.22278820 

Omicron is the evolutionarily most distinct SARS-CoV-2 variant of concern (VOC) to date. We report that Omicron BA.1 breakthrough infection in BNT162b2-vaccinated individuals resulted in strong neutralizing activity against Omicron BA.1, BA.2 and previous SARS-CoV-2 VOCs, but not against the Omicron sublineages BA.4 and BA.5. BA.1 breakthrough infection induced a robust recall response, primarily expanding BMEM cells against epitopes shared broadly amongst variants, rather than inducing BA.1-specific B cells. The vaccination-imprinted BMEM cell pool had sufficient plasticity to be remodeled by heterologous SARS-CoV-2 spike glycoprotein exposure. While selective amplification of BMEM cells recognizing shared epitopes allows for effective neutralization of most variants that evade previously established immunity, susceptibility to escape by variants that acquire alterations at hitherto conserved sites may be heightened.

Published in Science (June 2, 2022):

https://doi.org/10.1126/sciimmunol.abq2427 

BACKGROUND

Despite the high efficacy of the BNT162b2 messenger RNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rare breakthrough infections have been reported, including infections among health care workers. Data are needed to characterize these infections and define correlates of breakthrough and infectivity.

METHODS

At the largest medical center in Israel, we identified breakthrough infections by performing extensive evaluations of health care workers who were symptomatic (including mild symptoms) or had known infection exposure. These evaluations included epidemiologic investigations, repeat reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assays, antigen-detecting rapid diagnostic testing (Ag-RDT), serologic assays, and genomic sequencing. Correlates of breakthrough infection were assessed in a case–control analysis. We matched patients with breakthrough infection who had antibody titers obtained within a week before SARS-CoV-2 detection (peri-infection period) with four to five uninfected controls and used generalized estimating equations to predict the geometric mean titers among cases and controls and the ratio between the titers in the two groups. We also assessed the correlation between neutralizing antibody titers and N gene cycle threshold (Ct) values with respect to infectivity.

RESULTS

Among 1497 fully vaccinated health care workers for whom RT-PCR data were available, 39 SARS-CoV-2 breakthrough infections were documented. Neutralizing antibody titers in case patients during the peri-infection period were lower than those in matched uninfected controls (case-to-control ratio, 0.361; 95% confidence interval, 0.165 to 0.787). Higher peri-infection neutralizing antibody titers were associated with lower infectivity (higher Ct values). Most breakthrough cases were mild or asymptomatic, although 19% had persistent symptoms (>6 weeks). The B.1.1.7 (alpha) variant was found in 85% of samples tested. A total of 74% of case patients had a high viral load (Ct value, <30) at some point during their infection; however, of these patients, only 17 (59%) had a positive result on concurrent Ag-RDT. No secondary infections were documented.

CONCLUSIONS

Among fully vaccinated health care workers, the occurrence of breakthrough infections with SARS-CoV-2 was correlated with neutralizing antibody titers during the peri-infection period. Most breakthrough infections were mild or asymptomatic, although persistent symptoms did occur.

Published in NEJM (July 28, 2021):

https://doi.org/10.1056/NEJMoa2109072 

Associations between vaccine breakthrough cases and infection by SARS coronavirus 2 (SARS-CoV-2) variants have remained largely unexplored. Here we analyzed SARS-CoV-2 whole-genome sequences and viral loads from 1,373 persons with COVID-19 from the San Francisco Bay Area from February 1 to June 30, 2021, of which 125 (9.1%) were vaccine breakthrough infections. Fully vaccinated were more likely than unvaccinated persons to be infected by variants carrying mutations associated with decreased antibody neutralization (L452R, L452Q, E484K, and/or F490S) (78% versus 48%, p = 1.96e-08), but not by those associated with increased infectivity (L452R and/or N501Y) (85% versus 77%, p = 0.092). Differences in viral loads were non-significant between unvaccinated and fully vaccinated persons overall (p = 0.99) and according to lineage (p = 0.09 – 0.78). Viral loads were significantly higher in symptomatic as compared to asymptomatic vaccine breakthrough cases (p < 0.0001), and symptomatic vaccine breakthrough infections had similar viral loads to unvaccinated infections (p = 0.64).

In 5 cases with available longitudinal samples for serologic analyses, vaccine breakthrough infections were found to be associated with low or undetectable neutralizing antibody levels attributable to immunocompromised state or infection by an antibody-resistant lineage. These findings suggest that vaccine breakthrough cases are preferentially caused by circulating antibody-resistant SARS-CoV-2 variants, and that symptomatic breakthrough infections may potentially transmit COVID-19 as efficiently as unvaccinated infections, regardless of the infecting lineage.

Preprint available in medRxiv (August 25, 2021):

https://doi.org/10.1101/2021.08.19.21262139 

While COVID-19 vaccines are highly effective at preventing severe disease, hospitalization, and death from COVID-19 and also reduce the likelihood of mild or asymptomatic infection, a small share of fully vaccinated individuals do become infected, and some become hospitalized or have died. These rare occurrences are known as “breakthrough cases” which are to be expected, and historically known to occur with other vaccines as none is 100% effective.  The Centers for Disease Control and Prevention (CDC) currently monitors hospitalizations and deaths, from any cause, among fully vaccinated individuals with COVID-19, but not breakthrough infections, which it stopped monitoring as of May 1. CDC presents this data in aggregate at the national level but not by state, and there is no single, public repository for data by state or data on breakthrough infections, since the CDC stopped monitoring them. We therefore reviewed the websites and other official state sources for all 50 states and D.C. to see which are providing data on COVID-19 breakthrough cases, hospitalizations and deaths, how regularly, and what those data may tell us. We only used data from official state sources (we did not include data available only in news media reports, for example). Where a state did not provide comparable data on overall COVID-19 cases, hospitalizations, or deaths reported over the period in which it captured breakthrough events, we obtained data on cases and deaths from the Johns Hopkins University COVID-19 Dashboard and on hospitalizations from the U.S. Department of Health & Human Services for the appropriate period (see methods for more detail).

Importantly, not all hospitalizations and deaths of those fully vaccinated and diagnosed with COVID-19 are due to COVID-19 or have a known cause at the time of reporting. The CDC reports that as of July 19, of 5,601 hospitalized breakthrough cases, 27% were asymptomatic or not related to COVID-19 and of 1,141 fatal cases, 26% were asymptomatic or not related to COVID-19. States differ in whether they provide this detail. DC, for example, reports that as of July 11, 50% of hospitalized breakthrough cases were due to COVID-19, 19% were not, and 31% were of unknown reason. However, few states made these distinctions. Where they did, we only included breakthrough hospitalizations and deaths due to COVID-19. In other cases, some of these breakthrough events may be due to causes other than COVID-19. Overall, we find that:

• Half of states (25) report some data on COVID-19 breakthrough events (see Table 1). Twenty-four provide data on breakthrough cases, 19 on hospitalizations and on deaths.
• Fifteen of these states regularly update these data, often on a weekly basis. The rest use a different frequency, have one-time reports, have stopped updating, or have an unclear reporting frequency.
• The data reported from these states indicate that breakthrough cases, hospitalizations, and deaths are extremely rare events among those who are fully vaccinated against COVID-19 (see Figure 1). The rate of breakthrough cases reported among those fully vaccinated is well below 1% in all reporting states, ranging from 0.01% in Connecticut to 0.29% in Alaska.
•  
  • The hospitalization rate among fully vaccinated people with COVID-19 ranged from effectively zero (0.00%) in California, Delaware, D.C., Indiana, New Jersey, New Mexico, Vermont, and Virginia to 0.06% in Arkansas. (Note: Hospitalization may or may not have been due to COVID-19.)
  • The rates of death among fully vaccinated people with COVID-19 were even lower, effectively zero (0.00%) in all but two reporting states, Arkansas and Michigan where they were 0.01%. (Note: Deaths may or may not have been due to COVID-19.)

• Almost all (more than 9 in 10) COVID-19 cases, hospitalizations, and deaths have occurred among people who are unvaccinated or not yet fully vaccinated, in those states reporting breakthrough data (see Figure 2). 
  • The reported share of COVID-19 cases among those not fully vaccinated ranged from 94.1% in Arizona to 99.85% Connecticut.
  • The share of hospitalizations among those with COVID-19 who are not fully vaccinated ranged from in 95.02% in Alaska to 99.93% in New Jersey. (Note: Hospitalization may or may not have been due to COVID-19.)
  • The share of deaths among people with COVID-19 who are not fully vaccinated ranged from to 96.91% in Montana to 99.91% in New Jersey. (Note: Deaths may or may not have been due to COVID-19.)

Note that as more people get vaccinated, the share of cases, hospitalizations, and deaths accounted for by unvaccinated people will tend to fall, since there will be fewer unvaccinated people in the population. That will be true even if infection, hospitalization, and death from COVID-19 is still very rare among vaccinated people.

Implications

While information on breakthrough events is still limited and incomplete, this analysis of available state-level data indicates that COVID-19 breakthrough cases, and especially hospitalizations and deaths, among those who are fully vaccinated are rare occurrences in the United States. Moreover, this data indicate the vast majority of reported COVID-19 cases, hospitalizations, and deaths in U.S. are among those who are unvaccinated or not fully vaccinated. These findings echo the abundance of data demonstrating the effectiveness of currently authorized COVID-19 vaccines. Moving forward, particularly as the more transmissible Delta variant is now the dominant strain of COVID-19 circulating in the U.S., more robust state-level data will help to monitor ongoing vaccine effectiveness and inform discussions about booster vaccinations.

Published by Kaiser Family Foundation (July  30, 2021)

BACKGROUND

Despite the high efficacy of the BNT162b2 messenger RNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rare breakthrough infections have been reported, including infections among health care workers. Data are needed to characterize these infections and define correlates of breakthrough and infectivity.

METHODS

At the largest medical center in Israel, we identified breakthrough infections by performing extensive evaluations of health care workers who were symptomatic (including mild symptoms) or had known infection exposure. These evaluations included epidemiologic investigations, repeat reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assays, antigen-detecting rapid diagnostic testing (Ag-RDT), serologic assays, and genomic sequencing. Correlates of breakthrough infection were assessed in a case–control analysis. We matched patients with breakthrough infection who had antibody titers obtained within a week before SARS-CoV-2 detection (peri-infection period) with four to five uninfected controls and used generalized estimating equations to predict the geometric mean titers among cases and controls and the ratio between the titers in the two groups. We also assessed the correlation between neutralizing antibody titers and N gene cycle threshold (Ct) values with respect to infectivity.

RESULTS

Among 1497 fully vaccinated health care workers for whom RT-PCR data were available, 39 SARS-CoV-2 breakthrough infections were documented. Neutralizing antibody titers in case patients during the peri-infection period were lower than those in matched uninfected controls (case-to-control ratio, 0.361; 95% confidence interval, 0.165 to 0.787). Higher peri-infection neutralizing antibody titers were associated with lower infectivity (higher Ct values). Most breakthrough cases were mild or asymptomatic, although 19% had persistent symptoms (>6 weeks). The B.1.1.7 (alpha) variant was found in 85% of samples tested. A total of 74% of case patients had a high viral load (Ct value, <30) at some point during their infection; however, of these patients, only 17 (59%) had a positive result on concurrent Ag-RDT. No secondary infections were documented.

CONCLUSIONS

Among fully vaccinated health care workers, the occurrence of breakthrough infections with SARS-CoV-2 was correlated with neutralizing antibody titers during the peri-infection period. Most breakthrough infections were mild or asymptomatic, although persistent symptoms did occur.

Published July 29, 2021 in NEJM:

https://doi.org/10.1056/NEJMoa2109072

Severe forms of coronavirus disease (COVID-19) linked to high mortality rates might arise in a minority of fully-vaccinated individuals with many co-occurring medical conditions, finds a recent study by Israeli researchers published in the journal Clinical Microbiology and Infection.  In Phase III clinical trials, two mRNA COVID-19 vaccines (Pfizer/BioNTech's BNT162b2 and Moderna's mRNA-1273) were shown to be 94-95% effective in preventing symptomatic forms of the disease. Moreover, similar efficacy was observed in different age groups, as well as in those older than 75 and those with comorbidities. Israel's vaccination campaign was swift, effective, and had a significant impact on the local COVID-19 dynamics. Factors that played a huge role here were small geographical and population size, advanced informatization, as well as effective cooperation between the government and the community-based health funds.  However, there is not enough data on the nature of breakthrough infections with COVID-19 vaccines that we started to observe even in highly vaccinated populations like Israel.

Furthermore, we lack data on the clinical traits and serologic correlates of protection of individuals hospitalized with COVID-19 after they have received their jabs. According to the Israeli Ministry of Health registry, by the end of April 2021, a total of 397 fully vaccinated patients were hospitalized with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after their second vaccine dose – with 234 of them suffering severe COVID-19 and 90 of them succumbing to the disease. By using a subset of hospitalized patients, a research group led by Dr. Tal Brosh-Nissimov from the Samson Assuta Ashdod University Hospital in Israel aimed to characterize vaccinated and hospitalized patients with breakthrough COVID-19 infection, but also to define principal risk factors linked to poor outcomes in this group.

A multi-center cohort study

This study used a cohort approach to study patients in seventeen different hospitals. Individuals that were included in the study have received two doses of Pfizer/BioNTech vaccine, they were positive for SARS-CoV-2 on PCR test and were hospitalized in a COVID-19 unit. Furthermore, clinical data has been retrieved from patients' medical records in accordance with a predefined questionnaire. Alongside PCR testing, even viral genomic sequencing has been pursued in order to identify variants of concern in the samples. A mixture of either mechanical ventilation or in-hospital death has been considered as a poor outcome, which was the main interest of this study. On the other hand, a favorable outcome has been defined as patient discharge or hospitalization without the need for ventilation.

Breakthrough infections linked to comorbidities

From a total of 152 patients included in the study, poor outcome was observed in 38 of them and mortality rate reached 22%. The clinical profile of these individuals resembled other COVID-19 hospitalized patients, which means they were primarily older men with a plethora of comorbidities associated with COVID-19 severity. Nonetheless, comorbidities were more frequent in patients with vaccine breakthrough infections in comparison to a large case series on unvaccinated hospitalized patients – including hypertension, diabetes, heart failure, chronic kidney diseases, chronic lung diseases, dementia and cancer. Moreover, 40% of the patients were immunocompromised. Higher SARS-CoV-2 viral load was linked to a substantially higher risk of poor outcome, which was also increased (albeit not significantly) in patients receiving a specific treatment regimen with anti-CD20 monoclonal antibodies, as well as in patients with low titers of protective antibodies.

Implications for high-risk individuals

The results of this study clearly imply that a small minority of individuals fully vaccinated with Pfizer/BioNTech vaccine might still present with a severe SARS-CoV-2 infection and the need for in-patient care – despite the vaccine's high effectiveness. More specifically, the outcome of patients included in the study was comparable to that of non-vaccinated hospitalized COVID-19 patients. Such research endeavors will aid in developing guidance to improve the protection of such patients. In the meantime, we should be cognizant that mass vaccination (leading to herd immunity) is an optimal way to indirectly protect vulnerable individuals.

Research Cited Published in Clin. Microb. Infection (July 6, 2021):

https://doi.org/10.1016/j.cmi.2021.06.036