Prevention, screening and treatment are the three-level prevention and treatment system for malignant tumors. Persistent infection of high-risk HPV is the main cause of precancerous cervical lesions and cervical cancer.

Prevention, screening and treatment are the three-level prevention and treatment system for malignant tumors. Persistent infection of high-risk HPV is the main cause of precancerous cervical lesions and cervical cancer. The Food and Drug Administration (FDA) approved the HPV preventive vaccine quadrivalent HPV vaccine (i.e. Gardasil), bivalent HPV vaccine (i.e. Cervarix) and nine-valent HPV vaccine (i.e. Gardasil 9) in 2006, 2009 and 2014, respectively, and cervical cancer has thus become the first malignant tumor to enter primary prevention and treatment. China Food and Drug Administration (CFDA) approved the bivalent and quadrivalent HPV vaccine in 2016 and 2017, and the conditionally approved the nine-valent HPV vaccine in my country in 2018. With the widespread application of HPV vaccines, the incidence of cervical cancer will inevitably be greatly reduced. When clinicians conduct HPV vaccine-related consultation, education, application and popular science, in addition to positive publicity, they should pay attention to and correctly understand the possible adverse events and side reactions after HPV vaccination in order to ensure the safety of the vaccinated person. Adverse events of the

vaccine refer to adverse clinical events that occur during or after vaccination, and may not be causally related to vaccination. Adverse events involving any of the following outcomes are defined as serious adverse events, including death, life-threatening, persistent or significant disability or inability to work, congenital abnormalities or birth defects, hospitalization or extension of existing hospital stays. Adverse reactions of vaccines refer to adverse events that have been thoroughly investigated and identified by experts as having a clear causal relationship with vaccination. Side effects of vaccines, usually mild adverse reactions, are predictable and dosage-related toxic side effects. Side reactions after HPV vaccination include local redness, swelling and pain, as well as fever, headache, fatigue, nausea, and muscle and joint pain. Among them, the most common side reaction is local redness and swelling, which lasts for 1 to 2 days, which is usually very mild and can be relieved by itself.

1. Safety evaluation of HPV vaccine

The safety evaluation of the vaccine is divided into two stages: one is safety demonstration before marketization, and the other is safety monitoring after approval. Before it was launched, all 13 HPV vaccines were rigorous clinical trials. The research subjects of the quadrivalent vaccine covered 29,000 women and men, the bivalent vaccine covered 30,000 women and the nine-valent vaccine covered 15,000 women and men. The results show that all three HPV vaccines are safe and effective. After the

3 HPV vaccine was approved, the Centers for Disease Control and Prevention (CDC) and the FDA continued to monitor new or rare problems that may arise after vaccination. The three major vaccine safety monitoring systems used by the US CDC include the Vaccine Adverse Effect Reporting System (VAERS), the Vaccine Safety Datalink (VSD), and the Clinical Immunification Safety Assessment network (CISA network).

All countries have safety monitoring and adverse event reporting systems, and adverse event reports come from reports from the public, health agencies and vaccine manufacturers. There are limitations in monitoring data due to reports bias, inconsistent data quality and integrity, and lack of comparisons of unvaccinated control groups. After the health and epidemic prevention department receives the adverse event report, it organizes experts to review and review the cases to clarify whether there is a causal relationship between vaccination and adverse events.

2. Common adverse reactions of HPV vaccine

1. Local side reactions: Redness, swelling and pain are the most common local side reactions of HPV vaccine. Randomized controlled clinical trials before the HPV vaccine were approved showed that the incidence of local pain in tetravalent vaccine was 84%, higher than that of saline control group (49%) and aluminum control group (75%). In the clinical trials of 1106 women aged 18 to 45, the incidence of local pain, redness and swelling in the bivalent vaccine was 92.9%, 44.3% and 36.5%, respectively, and 71.6%, 25.6% and 21.8% of the tetravalent vaccine, respectively. The incidence of local side reactions of the bivalent vaccine was higher than that of the tetravalent vaccine, and the incidence of severe local pain in all women vaccinated with the bivalent or tetravalent vaccine was about 6%. The incidence of local side reactions of nine-valent vaccines is slightly higher than that of tetravalent vaccines (90.7% and 84.9% respectively).Among adolescents aged 9 to 15, the incidence of local side reactions among female vaccinated patients is higher than that of males.

2. Systemic side reactions: Systemic side reactions of HPV vaccine include fever, headache, dizziness, muscle and joint pain, gastrointestinal symptoms (nausea, vomiting, abdominal pain), which are mostly mild and are self-limiting. In clinical trials before the approval of the tetravalent HPV vaccine, the incidence of systemic side reactions was 10%, and the incidence of fever was only higher than that of the placebo control group (10.1% and 8.4%, respectively). The incidence of other mild systemic side reactions was 0.5% different from that of the control group; the incidence of systemic side reactions of bivalent and tetravalent vaccines was similar, but fatigue (49.8% and 39.8%, respectively) and muscle pain (27.6% and 19.6%, respectively) were more common in bivalent vaccines. The incidence of systemic side reactions of nine-valent and tetravalent vaccines is similar.

Like many other vaccines, fainting may occur after HPV vaccination. To prevent damage caused by fainting, the vaccinated person should lie down or sit while receiving the vaccine, and observe for 15 minutes before leaving. Given that syncope is the only safety risk signal found so far (i.e. the number of adverse events exceeds expected values), the US FDA has revised the vaccination guidelines for the quadrivalent HPV vaccine and advised physicians to be prepared to prevent falls and injuries caused by syncope. The US CDC also included this recommendation in the recommended guideline for HPV vaccines.

3. New chronic diseases after HPV vaccination

HPV vaccine clinical trials before approval showed that there was no significant difference between the HPV vaccine group and the placebo control group. After the HPV vaccine was launched, some adverse events of new chronic diseases after vaccination were received, including autoimmune diseases. On the one hand, the WHO said high-quality studies based on population safety monitoring data did not find evidence that HPV vaccination is associated with these new chronic diseases. On the other hand, VAERS received 48,852 adverse events after receiving any vaccine from women aged 6 to 39 years old from 2006 to 2014. The incidence of severe adverse events (including gastroenteritis, rheumatoid arthritis, thrombocytopenia, systemic lupus erythematosus, vasculitis, hair loss, central nervous system demyelination diseases, ovarian damage and irritable bowel syndrome) was significantly higher than that of other vaccinated patients. Therefore, more research is needed to reveal the relationship between HPV vaccines and new chronic diseases (including autoimmune diseases, etc.). Here are the five new chronic diseases after HPV vaccination that are most popular.

1. Chronic regional pain syndrome: Chronic regional pain syndrome (CRPS) is rare, manifested as persistent pain in the upper and lower limbs, hands and feet after limb injuries, often accompanied by swelling of the affected area, skin pigmentation and impaired motor function. In 2013, Japan reported 40 cases of peripheral sympathetic neurological disorders in adolescent women after receiving the bivalent HPV vaccine, 18 of which were consistent with the diagnosis of CRPS, resulting in the Japanese government suspending the recommendation of HPV vaccination, which has continued to this day.

Huygen et al. collected 17 cases of CRPS after bivalent HPV vaccination, of which 10 were from Japan (incidentally 0.14/100,000 doses) and 7 were from the UK (incidentally 0.08/100,000 doses). The published background incidence was used for observation and expected analysis, and a systematic review of safety monitoring and literature was conducted. The quantitative analysis of data did not find any connection between CRPS and bivalent HPV vaccination, and the actual incidence of CRPS was significantly lower than the expected value. In addition to HPV vaccine, CRPS has also been reported after other vaccines, which is speculated that it may be caused by minor trauma in the injection operation. From June 2006 to August 2015, the United States received more than 80 million doses of HPV vaccine, and VAERS received 22 reports of CRPS, including 21 quadrivalent vaccine and 1 bivalent vaccine. From December 1, 2014 to December 31, 2017, VAERS received only one report of CRPS after nine-valent vaccination. Moreover, due to incomplete information, the diagnosis of this case was unclear, and it was only a suspected diagnosis of CRPS. Therefore, regardless of whether there is a causal relationship between HPV vaccination and CRPS, the current data indicate that the incidence of this adverse event is extremely low.In November 2015, the European Medicines Agency (EMA) conducted a detailed review of the occurrence of CRPS in young women after HPV vaccination, and there was no evidence that there was a causal relationship between HPV vaccination and CRPS.

2. Guillain-Barre syndrome: Guillain-Barre syndrome (GBS) is a rare neurodemyelinating disease. The patient's immune system destroys its own nerve cells, causing weakening of muscle strength or even paralysis. Most patients can recover, but some patients have long-term damage to the nervous system. From August 2006 to December 2015, men and women aged 9 to 26 in the United States received a total of 2773,185 doses of tetravalent HPV vaccine, and VSD only received a report of GBS after vaccination for only one case of male GSD. From December 1, 2014 to December 31, 2017, the United States received a total of 29 million doses of nine-valent HPV vaccine. VAERS received 4 GBS reports, but VSD did not receive any related reports. A systematic review of the safety monitoring data of the bivalent HPV vaccine four years after its launch was conducted, and no necessary connection was found for vaccination and immune-related diseases, and the incidence of GBS was within the expected range of the population. Research in the UK also shows that women aged 12-18 have no increased risk of GBS. It can be seen that the risk of GBS after HPV vaccination is extremely low.

3. Orthostatic tachycardia syndrome: Postural orthostatic tachyardia syndrome (POTS) refers to the rapid increase in the heart rate when the position turns upright, often accompanied by dizziness or fainting, and the cause is unknown. Monitoring agencies in various countries have received reports of POTS after HPV vaccination, but they cannot derive the causal relationship between the two from single case reports or small case studies that lack comparison. From June 2006 to August 2015, the United States received more than 80 million doses of HPV vaccine. VAERS received 29 reports of POTS. It conducted a retrospective analysis of adverse events. No abnormalities or unexpected situations were found, and it did not constitute a safety problem. December 1, 2014-December 31, 2017, the United States received 29 million doses of nine-valent HPV vaccine, and VAERS received 17 reports of POTS, of which only 6 were fully or partially qualified for the diagnosis of POTS. In November 2015, EMA conducted a detailed retrospective analysis of the occurrence of POTS in young women after HPV vaccination, and there was no evidence that there was a causal relationship between vaccination and POTS.

4. Myalgic encephalomyelitis - Chronic fatigue syndrome: Myalgic encephalomyelitis (ME) - Chronic fatigue syndrome (CFS) is a complex disabling disease. The patient feels severe fatigue and does not improve significantly after rest. From June 2006 to August 2015, the United States received more than 80 million doses of tetravalent HPV vaccine, and VAERS received 20 reports of ME-CFS. The CDC conducted a retrospective analysis of adverse events and found no abnormalities or unexpected situations. A report released by the Norwegian Institute of Public Health in 2017 pointed out that women who received the HPV vaccine through the Norwegian National Immunization Program in 2009-2014 have not increased their risk of ME-CFS.

5. Premature ovarian failure: Clinical trials before the approval of HPV vaccine showed that there was no significant difference in amenorrhea among women in the HPV vaccine group and the placebo control group, and there were no reports of premature ovarian failure (POI). From the approval of the HPV vaccine to December 31, 2017, VAERS received a total of 3 reports of POIs after receiving the nine-valent HPV vaccine, all of which were false data. From approval to December 31, 2017, VAERS received a total of 17 reports of POIs after receiving the quadrivalent HPV vaccine, 15 of which were false data and 2 were confirmed as POIs, but after a retrospective analysis, it was found that the evidence of the vaccine causing POIs is very inaccurate. There are reports that it may be that the immunogenic substances of the HPV vaccine, the toxic effects caused by aluminum-containing adjuvants or the induced immune responses that destroy the ovaries and lead to POI, but the specific mechanism is unknown. Case reports also cannot deduce a causal relationship between HPV vaccine and POI, but should attract attention and help identify and deal with similar situations in the future.

4. Serious adverse events of HPV vaccine

In clinical trials before the approval of the HPV vaccine, no serious adverse events were found in the tetravalent and bivalent vaccines, and the incidence rate of nine-valent vaccines was less than 0.1%. As of December 2017, among the adverse event reports received by VAERS, the incidence of serious adverse events of tetravalent, divalent and nickelvalent HPV vaccines was 32/100,000 doses, 14/100,000 doses and 7/100,000 doses, respectively.

From December 1, 2014 to December 31, 2017, the United States received 29 million doses of nine-valent HPV vaccine. VAERS received 7 death reports, of which 2 were confirmed deaths, and the rest were false data. From June 2006 to August 2015, the United States received 80 million doses of HPV vaccine, and VAERS received 117 reports of deaths after quadrivalent vaccination, of which 51 confirmed deaths. The CDC conducted a careful investigation of each death, and there was no evidence of a causal relationship between HPV vaccination and death. VSD in the United States conducted a study to evaluate all deaths within 30 days after vaccination, and found that 76 deaths within 30 days after vaccination, including 13 deaths after tetravalent HPV vaccination, including 9 deaths due to external causes such as accidents, homicide or suicide. Two of the other 4 cases were not related to the vaccine, and two did not have sufficient evidence to confirm or exclude deaths caused by the vaccine. The mortality rate after vaccination was compared with the mortality rate caused by all causes nationwide in the United States, and it was found that the risk of death within 30 days after vaccination was not increased; clinical examinations also found no causal relationship between vaccination and death.

5. HPV vaccine and pregnancy

Due to the lack of high-quality controlled studies, HPV vaccine has not been approved for vaccination for pregnant women. However, some pregnant women do receive HPV vaccine because they don’t know they are pregnant. Follow-up of these pregnant women's pregnancy outcomes after receiving HPV vaccine, and found that there was no significant difference in the risk of adverse pregnancy outcomes such as spontaneous miscarriage, stillbirth, birth defects, babies less than gestational age, low birth weight, and premature birth compared with pregnant women who did not receive HPV vaccine. Therefore, even women who only learn to know about pregnancy after receiving the HPV vaccine do not need to panic.

6. Summary

Global Advisory Comnittee on Vaccine Safety (GACVS) is an independent clinical and scientific professional consulting agency that provides WHO with scientific and rigorous advice on vaccine safety issues, covering multiple vaccine fields including HPV vaccines. GACVS has reviewed and evaluated the safety of HPV vaccines in 2007, 2008, 2009, 2013, 2014 and 2015. Afterwards, a systematic review and analysis of safety monitoring data provided by vaccine manufacturers from the United States, Australia, Japan and other countries was conducted, and the safety of three HPV vaccines was reconfirmed in the latest document released in 2017. It is also pointed out that making decisions to stop recommending HPV vaccines based on unreliable evidence alone would seriously harm the public's health.

To sum up, it is safe to get the HPV vaccine at present. Slight side effects may be unavoidable, but they are all self-limiting. The incidence of new chronic diseases is extremely low, and there is no evidence that it has a clear correlation with HPV vaccine, but it should be taken seriously and monitored and further research is needed. Safety monitoring of HPV vaccine is very important. After receiving the adverse event report, you must carefully review and identify it to confirm whether there are abnormalities or unexpected situations; the monitoring data should be analyzed in depth to identify whether there is a causal relationship between vaccination and adverse events. This will better identify and deal with similar and new adverse events, and maximize the safety of vaccinated people.

Article excerpted from Chen Fei, Lu Yan, etc. Pay attention to and correctly understand the safety of HPV vaccine. Chinese Journal of Obstetrics and Gynecology, April 2019, Volume 54, Issue 4.