Topic: SARS-CoV-2 Reinfections & Country Updates

19^th June, 2021, Saturday, 9.30am-10.30am

Key points from the discussion

• #1. A presentation on “SARS-CoV-2 Reinfections” was given by Dr Jayanthi Shastri, Professor & Head, Dept. of Microbiology, TN Medical College & Nair Hospital, Mumbai, Lab Director - Molecular Diagnostic Reference Laboratory, Kasturba Hospital for Infectious Diseases

• It is very difficult to establish reinfection. The most important about diagnosing reinfection is molecular detection of the virus at two different time points (episodes) with an intervening negative test supported by viral genetic sequencing data rather than persistent viral carriage.

• The first challenge in detecting reinfection is with regard to logistics and capacity, such as banking samples from primary infection and performing viral genome sequencing. It is very difficult to get a sample beyond one month. Banking samples is not mandatory.

• Other challenges include limited availability of routine sequencing capabilities at hospital and public health laboratories, clinical and lab criteria must be used to prioritise suspected reinfection cases for detailed investigations. These challenges help to explain why very few cases have been described to date.

• As per CDC protocol, investigate for suspected SARS-CoV-2 re-infection, when duration >90 days since previous infection and Ct value <33 or duration since previous infection of 45-90 days and Ct value <33 and symptoms typical of Covid or contact with a confirmed case. An important caveat to these criteria is that they likely do not apply to immunocompromised individuals, who can have prolonged virus replication. It is challenging to sequence a sample with Ct values between 33 and 35; as per ICMR, sample with Ct value >35 is negative. Laboratory evidence of reinfection is observation of different clades between the first and second infection and/or detection of >2 nucleotide differences for every month separating the first and second samples

• As per US CDC guidelines for categorising reinfections based on genomic data, best evidence is differing clades between the first and second infection, ideally coupled with other evidence of actual infection (e.g., high viral titers in each sample, positive for sgmRNA, or culture); moderate evidence is >2 nucleotide differences per month* in consensus between sequences that meet quality metrics above, ideally coupled with other evidence of actual infection (e.g., high viral titers in each sample, positive for sgmRNA, or culture) and poor evidence but possible is ≤2 nucleotide differences per month in consensus between sequences along with clinical symptoms.

• ICMR has developed a working epidemiological case definition of SARS-CoV-2 re-infection to strengthen surveillance. Re-infection with SARS-CoV-2 was defined as two positive tests at an interval of at least 102 days with one negative RT PCR between the two episodes. The telephonic survey revealed that 4.5% of SARS-CoV-2 infected persons had reinfection. A vaccine breakthrough infection is defined as the detection of SARS-CoV-2 RNA or antigen in a respiratory specimen collected from a person ≥14 days after they have completed all recommended doses of a Covid-19 vaccine.

• In India, infections occurring at least 14 days after the second dose of Covishield or Covaxin are called breakthrough infections.

• INSACOG study found that delta variant has been over represented in breakthrough infections.

• VOCs appear to confer high risk of breakthrough infection.

• A case of a 61-year-old female doctor was also presented, who had total of 3 infections, 2 breakthrough infections and 2 reinfections. The second reinfection occurred within 19 days of the first reinfection. She had an asymptomatic SARS-CoV-2 infection in August 2020. Asymptomatic infection does not produce adequate amounts of neutralising antibodies. She had taken both doses of Covishield and seroconversion was documented by the detection of binding antibodies (anti-RBD IgG). First symptom onset was on April 10^th during the first breakthrough infection and first reinfection, RT PCR was positive for SARS-CoV-1, whole genome sequencing showed alpha variant. Subsequently, RT PCR was negative and all symptoms resolved. Then again on April 25^th, she reported symptoms during second breakthrough infection, second reinfection, PCR positive, whole genome sequencing showed delta variant. The patient had a close contact with a family member infected with delta variant. All the time, serology was positive for anti-RBD IgG.

• Re infections do occur, occasionally they may be severe.

• Breakthrough infections are occurring and most of them are with the variants of concern.

• A case of 2 breakthrough infections, which were also both reinfections in an individual who already had had asymptomatic infection last year, was presented.

• Breakthrough reinfections appear to be very rare and difficult to establish, but occasionally can lead to severe disease and hospitalization.

• Urgent need to ramp up sequencing facilities to prove breakthrough and reinfections, need high clinical index of suspicion.

• Do not disregard Covid-19 like symptoms in convalescent or vaccinated individuals.

• In immunocompromised patients, the shedding is prolonged. There is a scope for the variation of the virus in vivo. In such situation, reinfection may occur.

• Masks, social distancing, hand washing continue to be very important.

• Nanopore sequencing and the Illumina sequencing platforms are being used for genome sequencing in India. For Illumina sequencing, a Ct value of 30-32 is acceptable, while for nanopore sequencing, samples with a Ct value of only up to 25 are accepted. This is a big challenge as many reinfections are not being established.

• The case presented emphasises that there is a need to redefine reinfection. Variant of concern (VOC) is more important than the viral load in a breakthrough reinfection. In this case, reinfection occurred in 19 days.

• Three important driving factors for reinfection are direction infection from a patient (where the virus is replicating and the viral load is high), host immune system dysregulation (even though PCR is negative) and the VOC (which is escaping the immune system).

• The delta variant shows immune escape because a syncitium is formed in the epithelial cells and the virus remains sequestered. It therefore escapes the immune system and the circulating antibodies and is able to thrive.

• Different gene targets are being used in India for PCR. So, a Ct value of 35 is acceptable instead of lowering it. If mutation occurs at any other region of the virus, it is likely to be missed. The only answer is whole genome sequencing must be done on a number of positive samples.

• The second wave is showing a clear decline, especially in the north parts of India. The delta strain is still prevalent in some parts of south, east and north east of India. The total cases, which had gone up to 4 lakh per day, have come down to 50-60 lakhs per day. However, we need to be ready for the immune escape.

• Hence, breakthrough reinfection cases are very pertinent. Though they are minuscule, we need to be mindful of them.

• The delta variant is highly transmissible, it is rapidly recovering, a large percentage is asymptomatic and the case fatality rate is lower.

• Presence of binding antibodies does not confer protection. The critical value of neutralizing antibodies that is protective is yet to be established. Binding antibodies may give a false sense of security with regard to protection. Presence of antibodies does not take away the need for wearing masks.

#2. Country Updates

• South Africa: There is a third wave in the country. The number of daily cases is rising and has increased up to 17,000. More than 60 healthcare workers have been infected after J&J vaccine. Most had comorbidities. Genomic analysis showed delta variant infection. Vaccination is proceeding at a slow pace as there not enough doses. So far, 1.5 million have been vaccinated. No antibody tests are being done after the vaccine. The sputnik V vaccine is under review. There is a strict stage 3 lockdown in the country.

• Malaysia: VOCs are a cause of worry as there have been some cases of delta variant. The country is in total lockdown. There were more than 6000 cases in the last 24 hours. Pfizer and Sinovac vaccines are being used for vaccination, but there is shortage of vaccines.

• Bangladesh: There is a second wave; the border areas with India are a concern. There is a shortage of vaccines, so the vaccination is slow now.

• India: The number of daily cases has now decreased to around 60,000. The high death rates were a concern earlier, but it has reduced to 1300-1400 deaths per day. There is a clear cut decline across all parts of the country; a very good decline is seen in Delhi-NCR and North, a reasonable decline seen in Gujarat, MP and Karnataka; a thick tail seen in Maharashtra (Mumbai). The disease is still prevalent in AP, Tamil Nadu, Telangana, West Bengal and North East called the states of concern.

• Singapore: Lot of genomic analysis is being done in the country. There are 550 delta variant cases; 122 are imported and 400+ are community cases. Yesterday there were 20 cases. People coming into Singapore are quarantined for 21 days. Around 4 million people have been vaccinated with at least one dose; 2 million with 2 doses.

• Sweden: Sharp drop in patients after the third wave, including inpatients and ICU patients. Around half of the population has been vaccinated with at least one dose. Delta variant has been detected in the country and its spreading quite rapidly. The restrictions have not been relaxed. Borders have been opened, but vaccination certificates for full vaccination are required for this. Post-Covid symptoms are prevalent.

Participants

Member National Medical Associations

Dr Yeh Woei Chong, Singapore, Chair CMAAO; Dr Ravi Naidu, Malaysia, Immediate Past President CMAAO; Prof Ashraf Nizami, Pakistan, First Vice President CMAAO; Dr Heidi Stensmyren, Sweden, President-elect World Medical Association; Dr Salma Kundi, Pakistan; Dr Qaiser Sajjad, Pakistan; Dr Akhtar Hussain, South Africa; Dr Md Jamaluddin Chowdhury, Bangladesh

Invitees

Dr Veena Aggarwal, MD IJCP Group; Dr Jayanti Shastri, Mumbai, India; Dr Shashank Joshi, Mumbai, India; Dr Monica Vasudev, USA; Dr Mulazim Hussain Bukhari, Pakistan; Dr S Sharma, Editor IJCP Group; Dr Meenakshi Soni Barnwal, HCFI

Moderator

Mr Saurabh Aggarwal